Sulfonamido ether substituted imidazoquinolines

ABSTRACT

Imidazoquinoline and tetrahydroimidazoquinoline compounds that contain ether and sulfonamide or sulfamide functionality at the 1-position are useful as immune response modifiers. The compounds and compositions of the invention can induce the biosynthesis of various cytokines and are useful in the treatment of a variety of conditions including viral diseases and neoplastic diseases.

[0001] This application claims the benefit of previously filedProvisional Application Serial No. 60/254,218, filed on Dec. 8, 2000.

FIELD OF THE INVENTION

[0002] This invention relates to imidazoquinoline compounds that haveether and sulfonamide or sulfamide functionality at the 1-position, andto pharmaceutical compositions containing such compounds. A furtheraspect of this invention relates to the use of these compounds asimmunomodulators, for inducing cytokine biosynthesis in animals, and inthe treatment of diseases, including viral and neoplastic diseases.

BACKGROUND OF THE INVENTION

[0003] The first reliable report on the 1H-imidazo[4,5-c]quinoline ringsystem, Backman et al., J. Org. Chem. 15, 1278-1284 (1950) describes thesynthesis of1-(6-methoxy-8-quinolinyl)-2-methyl-1H-imidazo[4,5-c]quinoline forpossible use as an antimalarial agent. Subsequently, syntheses ofvarious substituted 1H-imidazo[4,5-c]quinolines were reported. Forexample, Jain et al., J. Med. Chem. 11, pp. 87-92 (1968), synthesizedthe compound 1-[2-(4-piperidyl)ethyl]-1H-imidazo[4,5-c]quinoline as apossible anticonvulsant and cardiovascular agent. Also, Baranov et al.,Chem. Abs. 85, 94362 (1976), have reported several2-oxoimidazo[4,5-c]quinolines, and Berenyi et al., J. Heterocyclic Chem.18, 1537-1540 (1981), have reported certain2-oxoimidazo[4,5-c]quinolines.

[0004] Certain 1H-imidazo[4,5-c]quinolin-4-amines and 1- and2-substituted derivatives thereof were later found to be useful asantiviral agents, bronchodilators and immunomodulators. These aredescribed in, inter alia, U.S. Pat. Nos. 4,689,338; 4,698,348;4,929,624; 5,037,986; 5,268,376; 5,346,905; and 5,389,640, all of whichare incorporated herein by reference.

[0005] There continues to be interest in the imidazoquinoline ringsystem. Certain 1H-imidazo[4,5-c]naphthyridine-4-amines,1H-imidazo[4,5-c]pyridin-4-amines, and1H-imidazo[4,5-c]quinolin-4-amines having an ether containingsubstituent at the 1 position are known. These are described in U.S.Pat. Nos. 5,268,376; 5,389,640; 5,494,916; and WO 99/29693.

[0006] There is a continuing need for compounds that have the ability tomodulate the immune response, by induction of cytokine biosynthesis orother mechanisms.

SUMMARY OF THE INVENTION

[0007] We have found a new class of compounds that are useful ininducing cytokine biosynthesis in animals. Accordingly, this inventionprovides imidazoquinoline-4-amine and tetrahydroimidazoquinoline-4-aminecompounds that have an ether and sulfonamide or sulfamide containingsubstituent at the 1-position. The compounds are defined by Formulas (I)and (II), which are defined in more detail infra. These compounds sharethe general structural formula

[0008] wherein X, R₁, R₂, and R are as defined herein for each class ofcompounds having Formulas (I) and (II).

[0009] The compounds of Formulas (I) and (II) are useful as immuneresponse modifiers due to their ability to induce cytokine biosynthesisand otherwise modulate the immune response when administered to animals.This makes the compounds useful in the treatment of a variety ofconditions such as viral diseases and tumors that are responsive to suchchanges in the immune response.

[0010] The invention further provides pharmaceutical compositionscontaining the immune response modifying compounds, and methods ofinducing cytokine biosynthesis in an animal, treating a viral infectionin an animal, and/or treating a neoplastic disease in an animal byadministering a compound of Formula (I) or (II) to the animal.

[0011] In addition, the invention provides methods of synthesizing thecompounds of the invention and novel intermediates useful in thesynthesis of these compounds.

DETAILED DESCRIPTION OF THE INVENTION

[0012] As mentioned earlier, we have found certain compounds that inducecytokine biosynthesis and modify the immune response in animals. Suchcompounds are represented by Formulas (I) and (II), shown below.

[0013] Imidazoquinoline compounds of the invention, which have ether andsulfonamide or sulfamide functionality at the 1-position are representedby Formula (I):

[0014] wherein:

[0015] X is —CHR₅—, —CHR₅-alkyl-, or —CHR₅-alkenyl-;

[0016] —R₁ is selected from the group consisting of:

[0017] —R₄—NR₃—SO₂—R₆-alkyl;

[0018] —R₄—NR₃—SO₂—R₆-alkenyl;

[0019] —R₄—NR₃—SO₂—R₆-aryl;

[0020] —R₄—NR₃—SO₂—R₆-heteroaryl;

[0021] —R₄—NR₃—SO₂—R₆-heterocyclyl;

[0022] —R₄—NR₃—SO₂—R₇;

[0023] —R₄—NR₃—SO₂—NR₅—R₆-alkyl;

[0024] —R₄—NR₃—SO₂—NR₅—R₆-alkenyl;

[0025] —R₄—NR₃—SO₂—NR₅—R₆-aryl;

[0026] —R₄—NR₃—SO₂—NR₅—R₆-heteroaryl;

[0027] —R₄—NR₃—SO₂—NR₅—R₆-heterocyclyl; and

[0028] —R₄—NR₃—SO₂—NH₂;

[0029] R₂ is selected from the group consisting of:

[0030] -hydrogen;

[0031] -alkyl;

[0032] -alkenyl;

[0033] -aryl;

[0034] -heteroaryl;

[0035] -heterocyclyl;

[0036] -alkyl-Y-alkyl;

[0037] -alkyl-Y-alkenyl;

[0038] -alkyl-Y-aryl; and

[0039] -alkyl or alkenyl substituted by one or more substituentsselected from the group consisting of:

[0040] —OH;

[0041] -halogen;

[0042] —N(R₅)₂;

[0043] —CO—N(R₅)₂;

[0044] —CO—C₁₋₁₀ alkyl;

[0045] —CO—O—C₁₋₁₀ alkyl;

[0046] —N₃;

[0047] -aryl;

[0048] -heteroaryl;

[0049] -heterocyclyl;

[0050] —CO-aryl; and

[0051] —CO-heteroaryl;

[0052] Y is —O— or —S(O)₀₋₂—;

[0053] R₃ is H, C₁₋₁₀ alkyl, or arylalkyl;

[0054] each R₄ is independently alkyl or alkenyl, which may beinterrupted by one or more —O— groups; or R₃ and R₄ can join together toform a ring;

[0055] each R₅ is independently H, C₁₋₁₀ alkyl, or C₂₋₁₀ alkenyl;

[0056] R₆ is a bond, alkyl, or alkenyl, which may be interrupted by oneor more —O— groups;

[0057] R₇ is C₁₋₁₀ alkyl; or R₃ and R₇ can join together to form a ring;

[0058] n is 0 to 4; and

[0059] each R present is independently selected from the groupconsisting of C₁₋₁₀ alkyl, C₁₋₁₀ alkoxy, hydroxy, halogen andtrifluoromethyl;

[0060] or a pharmaceutically acceptable salt thereof.

[0061] The invention also includes tetrahydroimidazoquinoline compoundsthat bear an ether and sulfanomide or sulfamide containing substituentat the 1-position. Such tetrahydroimidazoquinoline compounds arerepresented by Formula (II):

[0062] wherein:

[0063] X is —CHR₅—, —CHR₅-alkyl-, or —CHR₅-alkenyl-;

[0064] R₁ is selected from the group consisting of:

[0065] —R₄—NR₃—SO₂—R₆-alkyl;

[0066] —R₄—NR₃—SO₂—R₆-alkenyl;

[0067] —R₄—NR₃—SO₂—R₆-aryl;

[0068] —R₄—NR₃—SO₂—R₆-heteroaryl;

[0069] —R₄—NR₃—SO₂—R₆-heterocyclyl;

[0070] —R₄—NR₃—SO₂—R₇;

[0071] —R₄—NR₃—SO₂—NR₅—R₆-alkyl;

[0072] —R₄—NR₃—SO₂—NR₅—R₆-alkenyl;

[0073] —R₄—NR₃—SO₂—NR₅—R₆-aryl;

[0074] —R₄—NR₃—SO₂—NR₅—R₆-heteroaryl;

[0075] —R₄—NR₃—SO₂—NR₅—R₆-heterocyclyl; and

[0076] —R₄—NR₃—SO₂—NH₂;

[0077] R₂ is selected from the group consisting of:

[0078] -hydrogen;

[0079] -alkyl;

[0080] -alkenyl;

[0081] -aryl;

[0082] -heteroaryl;

[0083] -heterocyclyl;

[0084] -alkyl-Y-alkyl;

[0085] -alkyl-Y-alkenyl;

[0086] -alkyl-Y-aryl; and

[0087] -alkyl or alkenyl substituted by one or more substituentsselected from the group consisting of:

[0088] —OH;

[0089] -halogen;

[0090] —N(R₅)₂;

[0091] —CO—N(R₅)₂;

[0092] —CO—C₁₋₁₀ alkyl;

[0093] —CO—O—C₁₋₁₀ alkyl;

[0094] —N₃;

[0095] -aryl;

[0096] -heteroaryl;

[0097] -heterocyclyl;

[0098] —CO-aryl; and

[0099] —CO-heteroaryl;

[0100] Y is —O— or —S(O)₀₋₂—;

[0101] R₃ is H, C₁₋₁₀ alkyl, or arylalkyl;

[0102] each R₄ is independently alkyl or alkenyl, which may beinterrupted by one or more —O— groups; or R₃ and R₄ can join together toform a ring;

[0103] each R₅ is independently H, C₁₋₁₀ alkyl, or C₂₋₁₀ alkenyl;

[0104] R₆ is a bond, alkyl, or alkenyl, which may be interrupted by oneor more —O— groups;

[0105] R₇ is C₁₋₁₀ alkyl; or R₃ and R₇ can join together to form a ring;

[0106] n is 0 to 4; and

[0107] each R present is independently selected from the groupconsisting of C₁₋₁₀ alkyl, C₁₋₁₀ alkoxy, hydroxy, halogen, andtrifluoromethyl;

[0108] or a pharmaceutically acceptable salt thereof.

[0109] Preparation of the Compounds

[0110] Compounds of the invention can be prepared according to ReactionScheme I where R, R₁, R₂, X and n are as defined above.

[0111] In step (1) of Reaction Scheme I a 2,4-dichloro-3-nitroquinolineof Formula X is reacted with an amine of Formula R₁—O—X—NH₂ to provide a2-chloro-3-nitroquinolin-4-amine of Formula XI. The reaction can becarried out by adding the amine to a solution of a compound of Formula Xin a suitable solvent such as chloroform or dichloromethane andoptionally heating. Many quinolines of Formula XI are known or can beprepared using known synthetic methods, see for example, Andre et al.,U.S. Pat. No. 4,988,815 and references cited therein. Many amines ofFormula R₁—O—X—NH₂ are known; some are commercially available and otherscan by prepared using known synthetic methods.

[0112] In step (2) of Reaction Scheme I a2-chloro-3-nitroquinolin-4-amine of Formula XI is reduced to provide a2-chloroquinoline-3,4-diamine of Formula XII. Preferably, the reductionis carried out using a conventional heterogeneous hydrogenation catalystsuch as platinum on carbon or palladium on carbon. The reaction canconveniently be carried out on a Parr apparatus in a suitable solventsuch as ethanol, isopropanol or toluene.

[0113] In step (3) of Reaction Scheme I a 2-chloroquinoline-3,4-diamineof Formula XII is reacted with a carboxylic acid or an equivalentthereof to provide a 4-chloro-1H-imidazo[4,5-c]quinoline of FormulaXIII. Suitable equivalents to carboxylic acid include orthoesters and1,1-dialkoxyalkyl alkanoates. The carboxylic acid or equivalent isselected such that it will provide the desired R₂ substituent in acompound of Formula XIII. For example, triethyl orthoformate willprovide a compound where R₂ is hydrogen and triethyl orthoacetate willprovide a compound where R₂ is methyl. The reaction can be run in theabsence of solvent or in an inert solvent such as toluene. The reactionis run with sufficient heating to drive off any alcohol or water formedas a byproduct of the reaction.

[0114] Alternatively, step (3) can be carried out by (i) reacting thediamine of Formula XII with an acyl halide of Formula R₂C(O)Cl and then(ii) cyclizing. In part (i) the acyl halide is added to a solution ofthe diamine in an inert solvent such as acetonitrile or dichloromethane.The reaction can be carried out at ambient temperature. The product canbe isolated using conventional methods. In part (ii) the product of part(i) is heated in an alcoholic solvent in the presence of a base.Preferably the product of part (i) is refluxed in ethanol in thepresence of an excess of triethylamine or heated with methanolicammonia.

[0115] In step (4) of Reaction Scheme I a4-chloro-1H-imidazo[4,5-c]quinoline of Formula XIII is aminated toprovide a 1H-imidazo[4,5-c]quinolin-4-amine of Formula I. The reactionis carried out by heating (e.g., 125-175° C.) a compound of Formula XIIIunder pressure in a sealed reactor in the presence of a solution ofammonia in an alkanol. The product or a pharmaceutically acceptable saltthereof can be isolated using conventional methods.

[0116] Compounds of the invention containing a sulfonamide group can beprepared according to Reaction Scheme II where R, R₂, R₃, R₄, X and nare as defined above, BOC is tert-butoxycarbonyl and R₁₁ is —R₆-alkyl,—R₆-aryl, —R₆-heteroaryl or —R₆-heterocyclyl where R₆ is as definedabove.

[0117] In step (1) of Reaction Scheme II the amino group of anaminoalcohol of Formula XIV is protected with a tert-butoxycarbonylgroup. A solution of the aminoalcohol in tetrahydrofuran is treated withdi-tert-butyl dicarbonate in the presence of a base such as sodiumhydroxide. Many aminoalcohols of Formula XIV are commercially available;others can be prepared using known synthetic methods.

[0118] In step (2) of Reaction Scheme II a protected aminoalcohol ofFormula XV is converted to an iodide of Formula XVI. Iodine is added toa solution of triphenylphosphine and imidazole in dichloromethane; thena solution of a protected aminoalcohol of Formula XV in dichloromethaneis added. The reaction is carried out at ambient temperature.

[0119] In step (3) of Reaction Scheme II a1H-imidazo[4,5-c]quinolin-1-yl alcohol of Formula XVII is alkylated withan iodide of Formula XVI to provide a 1H-imidazo[4,5-c]quinolin-1-ylether of Formula XVIII. The alcohol of Formula XVII is reacted withsodium hydride in a suitable solvent such as N,N-dimethylformamide toform an alkoxide. The iodide is added to the alkoxide solution atambient temperature. After the addition is complete the reaction isstirred at an elevated temperature (˜100° C.). Many compounds of FormulaXVII are known, see for example, Gerster, U.S. Pat. No. 4,689,338;others can readily be prepared using known synthetic routes, see forexample, Gerster et al., U.S. Pat. No. 5,605,899 and Gerster, U.S. Pat.No. 5,175,296.

[0120] In step (4) of Reaction Scheme II a1H-imidazo[4,5-c]quinolin-1-yl ether of Formula XVIII is oxidized toprovide a 1H-imidazo[4,5-c]quinoline-5N-oxide of Formula XIX using aconventional oxidizing agent capable of forming N-oxides. Preferably asolution of a compound of Formula XVIII in chloroform is oxidized using3-chloroperoxybenzoic acid at ambient temperature.

[0121] In step (5) of Reaction Scheme II a1H-imidazo[4,5-c]quinoline-5N-oxide of Formula XIX is aminated toprovide a 1H-imidazo[4,5-c]quinolin-4-amine of Formula XX. Step (5)involves (i) reacting a compound of Formula XIX with an acylating agentand then (ii) reacting the product with an aminating agent. Part (i) ofstep (5) involves reacting an N-oxide of Formula XIX with an acylatingagent. Suitable acylating agents include alkyl- or arylsulfonylchlorides (e.g., benezenesulfonyl chloride, methanesulfonyl chloride,p-toluenesulfonyl chloride). Arylsulfonyl chlorides are preferred.Para-toluenesulfonyl chloride is most preferred. Part (ii) of step (5)involves reacting the product of part (i) with an excess of an aminatingagent. Suitable aminating agents include ammonia (e.g., in the form ofammonium hydroxide) and ammonium salts (e.g., ammonium carbonate,ammonium bicarbonate, ammonium phosphate). Ammonium hydroxide ispreferred. The reaction is preferably carried out by dissolving theN-oxide of Formula XIX in an inert solvent such as dichloromethane or1,2-dichloroethane with heating if necessary, adding the aminating agentto the solution, and then slowly adding the acylating agent. Optionallythe reaction can be carried out in a sealed pressure vessel at anelevated temperature (85-100°).

[0122] In step (6) of Reaction Scheme II the protecting group is removedby hydrolysis under acidic conditions to provide a1H-imidazo[4,5-c]quinolin-4-amine of Formula XXI. Preferably thecompound of Formula XX is treated with hydrochloric acid/ethanol atambient temperature or with gentle heating.

[0123] In step (7) of Reaction Scheme II a1H-imidazo[4,5-c]quinolin-4-amine of Formula XXI is converted to asulfonamide of Formula XXII which is a subgenus of Formula I usingconventional synthetic methods. For example, a compound of Formula XXIcan be reacted with a sulfonyl chloride of Formula R₁₁ S(O₂)Cl. Thereaction can be carried out by adding a solution of the sulfonylchloride in a suitable solvent such as dichloromethane or1-methyl-2-pyrrolidinone to a solution of a compound of Formula XXI atambient temperature. Alternatively, a compound of Formula XXI can bereacted with a sulfonic anhydride of Formula R₁₁S(O₂)OS(O₂)R₁₁. Thereaction can be run at ambient temperature in an inert solvent such asdichloromethane in the presence of a base such as pyridine orN,N-diisopropylethylamine. The product or a pharmaceutically acceptablesalt thereof can be isolated using conventional methods.

[0124] Compounds of the invention containing a sulfonamide group can beprepared according to Reaction Scheme III where R, R₂, R₃, R₄, R₁₁, Xand n are as defined above and BOC is tert-butoxycarbonyl.

[0125] In step (1) of Reaction Scheme III the amino group of anaminoalcohol of Formula XXIII is protected with a tert-butoxycarbonylgroup. A solution of the aminoalcohol in tetrahydrofuran is treated withdi-tert-butyl dicarbonate in the presence of a base such as sodiumhydroxide. Many aminoalcohols of Formula XXIII are commerciallyavailable; others can be prepared using known synthetic methods.

[0126] In step (2) of Reaction Scheme III a protected amino alcohol ofFormula XXIV is converted to a methanesulfonate of Formula XXV. Asolution of a compound of Formula XXIV in a suitable solvent such asdichloromethane is treated with methanesulfonyl chloride in the presenceof a base such as triethylamine. The reaction can be carried out at areduced temperature (0° C.).

[0127] In step (3a) of Reaction Scheme III a methanesulfonate of FormulaXXV is converted to an azide of Formula XXVI. Sodium azide is added to asolution of a compound of Formula XXV in a suitable solvent such asN,N-dimethylformamide or tetrahydrofuran. The reaction can be carriedout at an elevated temperature (80-100° C.).

[0128] In step (3b) of Reaction Scheme III a compound of Formula XXVI isalkylated with a halide of Formula Hal-R₃ to provide a compound ofFormula XXVII. In compounds where R₃ is hydrogen this step is omitted.The compound of Formula XXVI is reacted with sodium hydride in asuitable solvent such as N,N-dimethylformamide to form the anion andthen combined with the halide. The reaction can be carried out atambient temperature.

[0129] In step (4) of Reaction Scheme III an azide of Formula XXVI orXXVII is reduced to provide an amine of Formula XXVIII. Preferably, thereduction is carried out using a conventional heterogeneoushydrogenation catalyst such as palladium on carbon. The reaction canconveniently be carried out on a Parr apparatus in a suitable solventsuch as methanol or isopropanol.

[0130] In step (5) of Reaction Scheme III a 4-chloro-3-nitroquinoline ofFormula XXIX is reacted with an amine of Formula XXVIII to provide a3-nitroquinoline of Formula XXX. The reaction can be carried out byadding an amine of Formula XXVIII to a solution of a compound of FormulaXXIX in a suitable solvent such as dichloromethane in the presence of abase such as triethylamine. Many quinolines of Formula XXIX are knowncompounds or can be prepared using known synthetic methods, see forexample, U.S. Pat. No. 4,689,338 and references cited therein.

[0131] In step (6) of Reaction Scheme III a 3-nitroquinoline of FormulaXXX is reduced to provide a 3-aminoquinoline of Formula XXXI.Preferably, the reduction is carried out using a conventionalheterogeneous hydrogenation catalyst such as platinum on carbon. Thereaction can conveniently be carried out on a Parr apparatus in asuitable solvent such as toluene.

[0132] In step (7) of Reaction Scheme III a compound of Formula XXXI isreacted with a carboxylic acid or an equivalent thereof to provide a1H-imidazo[4,5-c]quinoline of Formula XVIII. Suitable equivalents tocarboxylic acid include orthoesters, and 1,1-dialkoxyalkyl alkanoates.The carboxylic acid or equivalent is selected such that it will providethe desired R₂ substituent in a compound of Formula XVIII. For example,triethyl orthoformate will provide a compound where R₂ is hydrogen andtriethyl orthovalerate will provide a compound where R₂ is butyl. Thereaction can be run in the absence of solvent or in an inert solventsuch as toluene. The reaction is run with sufficient heating to driveoff any alcohol or water formed as a byproduct of the reaction.Optionally a catalytic amount of pyridine hydrochloride can be included.

[0133] Alternatively, step (7) can be carried out by (i) reacting acompound of Formula XXXI with an acyl halide of Formula R₂C(O)Cl andthen (ii) cyclizing. In part (i) the acyl halide is added to a solutionof a compound of Formula XXXI in an inert solvent such as acetonitrileor dichloromethane. The reaction can be carried out at ambienttemperature or at a reduced temperature. In part (ii) the product ofpart (i) is heated in an alcoholic solvent in the presence of a base.Preferably the product of part (i) is refluxed in ethanol in thepresence of an excess of triethylamine or heated with methanolicammonia.

[0134] Steps (8), (9), (10) and (11) are carried out in the same manneras steps (4), (5), (6) and (7) of Reaction Scheme II.

[0135] Compounds of the invention containing a sulfamide group can beprepared according to Reaction Scheme IV where R, R₂, R₃, R₄, R₅, R₁₁, Xand n are as defined above.

[0136] In step (1) of Reaction Scheme IV a1H-imidazo[4,5-c]quinolin-4-amine of Formula XXI is reacted withsulfuryl chloride to generate in situ a sulfamoyl chloride of FormulaXXXII. The reaction can be carried out by adding a solution of sulfurylchloride in dichloromethane to a solution of a compound of Formula XXIin dichloromethane in the presence of 1 equivalent of4-(dimethylamino)pyridine. The reaction is preferably carried out at areduced temperature (−78° C.).

[0137] In step (2) of Reaction Scheme IV an amine of Formula HNR₅R₁₁ isreacted with the sulfamoyl chloride of Formula XXXII to provide asulfamide of Formula XXXIII which is a subgenus of Formula I. Thereaction can be carried out by adding a solution containing 2equivalents of the amine and 2 equivalents of triethylamine indichloromethane to the reaction mixture from step (1). The addition ispreferably carried out at a reduced temperature (−78° C.). After theaddition is complete the reaction mixture can be allowed to warm toambient temperature. The product or a pharmaceutically acceptable saltthereof can be isolated using conventional methods.

[0138] Compounds of the invention can be prepared according to ReactionScheme V where R, R₂, R₃, R₄, R₁₁, X and n are as defined above.

[0139] In step (1) of Reaction Scheme V a1H-imidazo[4,5-c]quinolin-4-amine of Formula XXI is reduced to provide a6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amine of Formula XXXIV.Preferably the reduction is carried out by suspending or dissolving acompound of Formula XXI in trifluoroacetic acid, adding a catalyticamount of platinum (IV) oxide, and then hydrogenating. The reaction canbe conveniently carried out in a Parr apparatus.

[0140] Step (2) is carried out in the same manner as step (7) ofReaction Scheme II to provide a6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amine of Formula XXXVwhich is a subgenus of Formula II. The product or a pharmaceuticallyacceptable salt thereof can be isolated using conventional methods.

[0141] Compounds of the invention containing a sulfamide group can beprepared according to Reaction Scheme VI where R, R₂, R₃, R₄, R₅, R₁₁, Xand n are as defined above.

[0142] In step (1) of Reaction Scheme VI a1H-imidazo[4,5-c]quinolin-4-amine of Formula XXXIV is reacted withsulfuryl chloride to generate in situ a sulfamoyl chloride of FormulaXXXVI. The reaction can be carried out by adding a solution of sulfurylchloride in dichloromethane to a solution of a compound of Formula XXXIVin dichloromethane in the presence of 1 equivalent of4-(dimethylamino)pyridine. The reaction is preferably carried out at areduced temperature (−78° C.).

[0143] In step (2) of Reaction Scheme VI an amine of Formula HNR₅R₁₁ isreacted with the sulfamoyl chloride of Formula XXXVI to provide asulfamide of Formula XXXVII which is a subgenus of Formula II. Thereaction can be carried out by adding a solution containing 2equivalents of the amine and 2 equivalents of triethylamine indichloromethane to the reaction mixture from step (1). The addition ispreferably carried out at a reduced temperature (−78° C.). After theaddition is complete the reaction mixture can be allowed to warm toambient temperature. The product or a pharmaceutically acceptable saltthereof can be isolated using conventional methods.

[0144] The invention also provides novel compounds useful asintermediates in the synthesis of the compounds of Formulas (I) and(II). These intermediate compounds have the structural Formula (III).

[0145] wherein

[0146] X is —CHR₅—, —CHR₅-alkyl-, or —CHR₅-alkenyl-;

[0147] R₁ is selected from the group consisting of:

[0148] —R₄—NR₃—SO₂—R₆-alkyl;

[0149] —R₄—NR₃—SO₂—R₆-alkenyl;

[0150] —R₄—NR₃—SO₂—R₆-aryl;

[0151] —R₄—NR₃—SO₂—R₆-heteroaryl;

[0152] —R₄—NR₃—SO₂—R₆-heterocyclyl;

[0153] —R₄—NR₃—SO₂—R₇;

[0154] —R₄—NR₃—SO₂—NR₅—R₆-alkyl;

[0155] —R₄—NR₃—SO₂—NR₅—R₆-alkenyl;

[0156] —R₄—NR₃—SO₂—NR₅—R₆-aryl;

[0157] —R₄—NR₃—SO₂—NRs—R₆-heteroaryl;

[0158] —R₄—NR₃—SO₂—NR₅-R₆-heterocyclyl; and

[0159] —R₄—NR₃—SO₂—NH₂;

[0160] R₂ is selected from the group consisting of:

[0161] -hydrogen;

[0162] -alkyl;

[0163] -alkenyl;

[0164] -aryl;

[0165] -heteroaryl;

[0166] -heterocyclyl;

[0167] -alkyl-Y-alkyl;

[0168] -alkyl-Y-alkenyl;

[0169] -alkyl-Y-aryl; and

[0170] -alkyl or alkenyl substituted by one or more substituentsselected from the group consisting of:

[0171] —OH;

[0172] -halogen;

[0173] —N(R₅)₂;

[0174] —CO—N(R₅)₂;

[0175] —CO—C₁₋₁₀ alkyl;

[0176] —CO—O—C₁₋₁₀ alkyl;

[0177] —N₃;

[0178] -aryl;

[0179] -heteroaryl;

[0180] -heterocyclyl;

[0181] —CO-aryl; and

[0182] —CO-heteroaryl;

[0183] Y is —O— or —S(O)₀₋₂—;

[0184] R₃ is H, C₁₋₁₀ alkyl, or arylalkyl;

[0185] each R₄ is independently alkyl or alkenyl, which may beinterrupted by one or more —O— groups; or R₃ and R₄ can join to form aring;

[0186] each R₅ is independently H, C₁₋₁₀ alkyl, or C₂₋₁₀ alkenyl;

[0187] R₆ is a bond, or is alkyl or alkenyl, which may be interrupted byone or more —O— groups;

[0188] R₇ is C₁₋₁₀ alkyl; or R₃ and R₇ can join together to form a bond;

[0189] n is 0 to 4; and

[0190] each R present is independently selected from the groupconsisting of C₁₋₁₀ alkyl, C₁₋₁₀ alkoxy, hydroxy, halogen andtrifluoromethyl;

[0191] or a pharmaceutically acceptable salt thereof.

[0192] As used herein, the terms “alkyl”, “alkenyl” and the prefix“alk-” are inclusive of both straight chain and branched chain groupsand of cyclic groups, i.e. cycloalkyl and cycloalkenyl. Unless otherwisespecified, these groups contain from 1 to 20 carbon atoms, with alkenylgroups containing from 2 to 20 carbon atoms. Preferred groups have atotal of up to 10 carbon atoms. Cyclic groups can be monocyclic orpolycyclic and preferably have from 3 to 10 ring carbon atoms. Exemplarycyclic groups include cyclopropyl, cyclopropylmethyl, cyclopentyl,cyclohexyl and adamantyl.

[0193] In addition, the alkyl and alkenyl portions of —X— groups can beunsubstituted or substituted by one or more substituents, whichsubstituents are selected from the groups consisting of alkyl, alkenyl,aryl, heteroaryl, heterocyclyl, arylalkyl, heteroarylalkyl, andheterocyclylalkyl.

[0194] The term “haloalkyl” is inclusive of groups that are substitutedby one or more halogen atoms, including perfluorinated groups. This isalso true of groups that include the prefix “halo-”. Examples ofsuitable haloalkyl groups are chloromethyl, trifluoromethyl, and thelike.

[0195] The term “aryl” as used herein includes carbocyclic aromaticrings or ring systems. Examples of aryl groups include phenyl, naphthyl,biphenyl, fluorenyl and indenyl. The term “heteroaryl” includes aromaticrings or ring systems that contain at least one ring hetero atom (e.g.,O, S, N). Suitable heteroaryl groups include furyl, thienyl, pyridyl,quinolinyl, isoquinolinyl, indolyl, isoindolyl, triazolyl, pyrrolyl,tetrazolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, benzofuranyl,benzothiophenyl, carbazolyl, benzoxazolyl, pyrimidinyl, quinoxalinyl,benzoimidazolyl, benzothiazolyl, naphthyridinyl, isoxazolyl,isothiazolyl, quinazolinyl, purinyl, and so on.

[0196] “Heterocyclyl” includes non-aromatic rings or ring systems thatcontain at least one ring hetero atom (e.g., O, S, N) and includes allof the fully saturated and partially unsaturated derivatives of theabove mentioned heteroaryl groups. Exemplary heterocyclic groups includepyrrolidinyl, tetrahydrofuranyl, morpholinyl, thiomorpholinyl,piperidinyl, piperazinyl, thiazolidinyl, imidazolidinyl, and the like.

[0197] The aryl, heteroaryl, and heterocyclyl groups can beunsubstituted or substituted by one or more substituents independentlyselected from the group consisting of alkyl, alkoxy, alkylthio,haloalkyl, haloalkoxy, haloalkylthio, halogen, nitro, hydroxy, mercapto,cyano, carboxy, formyl, aryl, aryloxy, arylthio, arylalkoxy,arylalkylthio, heteroaryl, heteroaryloxy, heteroarylthio,heteroarylalkoxy, heteroarylalkylthio, amino, alkylamino, dialkylamino,heterocyclyl, heterocycloalkyl, alkylcarbonyl, alkenylcarbonyl,alkoxycarbonyl, haloalkylcarbonyl, haloalkoxycarbonyl,alkylthiocarbonyl, arylcarbonyl, heteroarylcarbonyl, aryloxycarbonyl,heteroaryloxycarbonyl, arylthiocarbonyl, heteroarylthiocarbonyl,alkanoyloxy, alkanoylthio, arylcarbonyloxy, arylcarbonylthio,arylcarbonylamino, alkylaminosulfonyl, alkylsulfonyl, arylsulfonyl,heteroarylsulfonyl, aryldiazinyl, alkylsulfonylamino, arylsulfonylamino,arylalkylsulfonylamino, alkylcarbonylamino, alkenylcarbonylamino,arylcarbonylamino, arylalkylcarbonylamino, heteroarylcarbonylamino,heteroarylalkycarbonylamino, alkylsulfonylamino, alkenylsulfonylamino,arylsulfonylamino, arylalkylsulfonylamino, heteroarylsulfonylamino,heteroarylalkylsulfonylamino, alkylaminocarbonylamino,alkenylaminocarbonylamino, arylaminocarbonylamino,arylalkylaminocarbonylamino, heteroarylaminocarbonylamino,heteroarylalkylcarbonylamino and, in the case of heterocyclyl, oxo. Ifany other groups are identified as being “substituted” or “optionallysubstituted”, then those groups can also be substituted by one or moreof the above enumerated substituents.

[0198] Certain substituents are generally preferred. For example,preferred RI groups include —R₄—NR₃—SO₂—R₆-alkyl, —R₄—NR₃—SO₂—R₆-aryl,and —R₄—NR₃—SO₂—R₆-heteroaryl wherein the alkyl, aryl and heteroarylgroups can be unsubstituted or substituted and R₄ is preferably ethyleneor n-butylene. Thiophene and quinoline are preferred heteroaryl groupsPreferably no R substituents are present (i.e., n is 0). Preferred R₂groups include hydrogen, alkyl groups having 1 to 4 carbon atoms (i.e.,methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, andcyclopropylmethyl), methoxyethyl, and ethoxymethyl. For substitutedgroups such as substituted alkyl or substituted aryl groups, preferredsubstituents include halogen, nitrile, methoxy, trifluoromethyl, andtrifluoromethoxy. One or more of these preferred substituents, ifpresent, can be present in the compounds of the invention in anycombination.

[0199] The invention is inclusive of the compounds described herein inany of their pharmaceutically acceptable forms, including isomers (e.g.,diastereomers and enantiomers), salts, solvates, polymorphs, and thelike. In particular, if a compound is optically active, the inventionspecifically includes each of the compound's enantiomers as well asracemic mixtures of the enantiomers.

[0200] Pharmaceutical Compositions and Biological Activity

[0201] Pharmaceutical compositions of the invention contain atherapeutically effective amount of a compound of the invention asdescribed above in combination with a pharmaceutically acceptablecarrier.

[0202] The term “a therapeutically effective amount” means an amount ofthe compound sufficient to induce a therapeutic effect, such as cytokineinduction, antitumor activity, and/or antiviral activity. Although theexact amount of active compound used in a pharmaceutical composition ofthe invention will vary according to factors known to those of skill inthe art, such as the physical and chemical nature of the compound, thenature of the carrier, and the intended dosing regimen, it isanticipated that the compositions of the invention will containsufficient active ingredient to provide a dose of about 100 ng/kg toabout 50 mg/kg, preferably about 10 μg/kg to about 5 mg/kg, of thecompound to the subject. Any of the conventional dosage forms may beused, such as tablets, lozenges, parenteral formulations, syrups,creams, ointments, aerosol formulations, transdermal patches,transmucosal patches and the like.

[0203] The compounds of the invention can be administered as the singletherapeutic agent in the treatment regimen, or the compounds of theinvention may be administered in combination with one another or withother active agents, including additional immune response modifiers,antivirals, antibiotics, etc.

[0204] The compounds of the invention have been shown to induce theproduction of certain cytokines in experiments performed according tothe tests set forth below. These results indicate that the compounds areuseful as immune response modifiers that can modulate the immuneresponse in a number of different ways, rendering them useful in thetreatment of a variety of disorders.

[0205] Cytokines whose production may be induced by the administrationof compounds according to the invention generally include interferon-α(IFN-α) and/or tumor necrosis factor-α (TNF-α) as well as certaininterleukins (IL). Cytokines whose biosynthesis may be induced bycompounds of the invention include IFN-α, TNF-α, IL-1, IL-6, IL-10 andIL-12, and a variety of other cytokines. Among other effects, these andother cytokines can inhibit virus production and tumor cell growth,making the compounds useful in the treatment of viral diseases andtumors. Accordingly, the invention provides a method of inducingcytokine biosynthesis in an animal comprising administering an effectiveamount of a compound or composition of the invention to the animal.

[0206] Certain compounds of the invention have been found topreferentially induce the expression of IFN-α in a population ofhematopoietic cells such as PBMCs (peripheral blood mononuclear cells)containing pDC2 cells (precursor dendritic cell-type 2) withoutconcomitant production of significant levels of inflammatory cytokines.

[0207] In addition to the ability to induce the production of cytokines,the compounds of the invention affect other aspects of the innate immuneresponse. For example, natural killer cell activity may be stimulated,an effect that may be due to cytokine induction. The compounds may alsoactivate macrophages, which in turn stimulates secretion of nitric oxideand the production of additional cytokines. Further, the compounds maycause proliferation and differentiation of B-lymphocytes.

[0208] Compounds of the invention also have an effect on the acquiredimmune response. For example, although there is not believed to be anydirect effect on T cells or direct induction of T cell cytokines, theproduction of the T helper type 1 (Th1) cytokine IFN-γ is inducedindirectly and the production of the T helper type 2 (Th2) cytokinesIL-4, IL-5 and IL-13 are inhibited upon administration of the compounds.This activity means that the compounds are useful in the treatment ofdiseases where upregulation of the Th1 response and/or downregulation ofthe Th2 response is desired. In view of the ability of compounds of theinvention to inhibit the Th2 immune response, the compounds are expectedto be useful in the treatment of atopic diseases, e.g., atopicdermatitis, asthma, allergy, allergic rhinitis; systemic lupuserythematosis; as a vaccine adjuvant for cell mediated immunity; andpossibly as a treatment for recurrent fungal diseases and chlamydia.

[0209] The immune response modifying effects of the compounds make themuseful in the treatment of a wide variety of conditions. Because oftheir ability to induce the production of cytokines such as IFN-α and/orTNF-α, the compounds are particularly useful in the treatment of viraldiseases and tumors. This immunomodulating activity suggests thatcompounds of the invention are useful in treating diseases such as, butnot limited to, viral diseases including genital warts; common warts;plantar warts; Hepatitis B; Hepatitis C; Herpes Simplex Virus Type I andType II; molluscum contagiosum; variola, particularly variola major;HIV; CMV; VZV; rhinovirus; adenovirus; influenza; and para-influenza;intraepithelial neoplasias such as cervical intraepithelial neoplasia;human papillomavirus (HPV) and associated neoplasias; fungal diseases,e.g. candida, aspergillus, and cryptococcal meningitis; neoplasticdiseases, e.g., basal cell carcinoma, hairy cell leukemia, Kaposi'ssarcoma, renal cell carcinoma, squamous cell carcinoma, myelogenousleukemia, multiple myeloma, melanoma, non-Hodgkin's lymphoma, cutaneousT-cell lymphoma, and other cancers; parasitic diseases, e.g.pneumocystis carnii, cryptosporidiosis, histoplasmosis, toxoplasmosis,trypanosome infection, and leishmaniasis; and bacterial infections,e.g., tuberculosis, and mycobacterium avium. Additional diseases orconditions that can be treated using the compounds of the inventioninclude actinic keratosis; eczema; eosinophilia; essentialthrombocythaemia; leprosy; multiple sclerosis; Ommen's syndrome; discoidlupus; Bowen's disease; Bowenoid papulosis; alopecia areata; theinhibition of keloid formation after surgery and other types ofpost-surgical scars. In addition, these compounds could enhance orstimulate the healing of wounds, including chronic wounds. The compoundsmay be useful for treating the opportunistic infections and tumors thatoccur after suppression of cell mediated immunity in, for example,transplant patients, cancer patients and HIV patients.

[0210] An amount of a compound effective to induce cytokine biosynthesisis an amount sufficient to cause one or more cell types, such asmonocytes, macrophages, dendritic cells and B-cells to produce an amountof one or more cytokines such as, for example, IFN-α, TNF-α, IL-1, IL-6,IL-10 and IL-12 that is increased over the background level of suchcytokines. The precise amount will vary according to factors known inthe art but is expected to be a dose of about 100 ng/kg to about 50mg/kg, preferably about 10 μg/kg to about 5 mg/kg. The invention alsoprovides a method of treating a viral infection in an animal and amethod of treating a neoplastic disease in an animal comprisingadministering an effective amount of a compound or composition of theinvention to the animal. An amount effective to treat or inhibit a viralinfection is an amount that will cause a reduction in one or more of themanifestations of viral infection, such as viral lesions, viral load,rate of virus production, and mortality as compared to untreated controlanimals. The precise amount will vary according to factors known in theart but is expected to be a dose of about 100 ng/kg to about 50 mg/kg,preferably about 10 μg/kg to about 5 mg/kg. An amount of a compoundeffective to treat a neoplastic condition is an amount that will cause areduction in tumor size or in the number of tumor foci. Again, theprecise amount will vary according to factors known in the art but isexpected to be a dose of about 100 ng/kg to about 50 mg/kg, preferablyabout 10 μg/kg to about 5 mg/kg.

[0211] The invention is further described by the following examples,which are provided for illustration only and are not intended to belimiting in any way.

[0212] In the examples below some of the compounds were purified usingsemi-preparative HPLC. A Waters Fraction Lynx automated purificationsystem was used. The semi-prep HPLC fractions were analyzed using aMicromass LC-TOFMS and the appropriate fractions were combined andcentrifuge evaporated to provide the trifluoroacetate salt of thedesired compound.

[0213] Column: Phenomenex Luna C18(2), 10×50 mm, 5 micron particle size,100 Å pore; flow rate: 25 mL/min.; gradient elution from 5-65% B in 4min., then 65 to 95% B in 0.1 min, then hold at 95% B for 0.4 min.,where A=0.05% trifluoroacetic acid/water and B=0.05% trifluoroaceticacid/acetonitrile; fraction collection by mass-selective triggering.

EXAMPLE 1N-(2-{2-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl)methanesulfonamide

[0214]

[0215] Part A

[0216] A solution of 2-(2-aminoethoxy)ethanol (29.0 g, 0.276 mol) in 180mL of tetrahydrofuran (THF), under N₂, was cooled to 0° C. and treatedwith 140 mL of 2N NaOH solution. A solution of di-tert-butyl dicarbonate(60.2 g, 0.276 mol) in 180 mL of THF was then added dropwise over 1 h tothe rapidly stirred solution. The reaction mixture was then allowed towarm to room temperature and was stirred an additional 18 h. The THF wasthen removed under reduced pressure and the remaining aqueous slurry wasbrought to pH 3 by addition of 150 mL of 1M H₂SO₄ solution. This wasthen extracted with ethyl acetate (300 mL, 100 mL) and the combinedorganic layers were washed with H₂O (2×) and brine. The organic portionwas dried over Na₂SO₄ and concentrated to give tert-butyl2-(2-hydroxyethoxy)ethylcarbamate as a colorless oil (47.1 g).

[0217] Part B

[0218] A rapidly stirred solution of tert-butyl2-(2-hydroxyethoxy)ethylcarbamate (47.1 g, 0.230 mol) in 1 L ofanhydrous CH₂Cl₂ was cooled to 0° C. under N₂ and treated withtriethylamine (48.0 mL, 0.345 mol). Methanesulfonyl chloride (19.6 mL,0.253 mol) was then added dropwise over 30 min. The reaction mixture wasthen allowed to warm to room temperature and was stirred an additional22 h. The reaction was quenched by addition of 500 mL saturated NaHCO₃solution and the organic layer was separated. The organic phase was thenwashed with H₂O (3×500 mL) and brine. The organic portion was dried overNa₂SO₄ and concentrated to give2-{2-[(tert-butoxycarbonyl)amino]ethoxy}ethyl methanesulfonate as abrown oil (63.5 g).

[0219] Part C

[0220] A stirred solution of2-{2-[(tert-butoxycarbonyl)amino]ethoxy}ethyl methanesulfonate (63.5 g,0.224 mol) in 400 mL of N,N-dimethylformamide (DMF) was treated withNaN₃ (16.1 g, 0.247 mol) and the reaction mixture was heated to 90° C.under N₂. After 5 h, the solution was cooled to room temperature andtreated with 500 mL of cold H₂O. The reaction mixture was then extractedwith Et₂O (3×300 mL). The combined organic extracts were washed with H₂O(4×100 mL) and brine (2×100 mL). The organic portion was dried overMgSO₄ and concentrated to give 52.0 g of tert-butyl2-(2-azidoethoxy)ethylcarbamate as a light brown oil.

[0221] Part D

[0222] A solution of tert-butyl 2-(2-azidoethoxy)ethylcarbamate (47.0 g,0.204 mol) in MeOH was treated with 4 g of 10% Pd on carbon and shakenunder H₂ (3 Kg/cm²) for 24 h. The solution was then filtered through aCelite pad and concentrated to give 35.3 g of crude tert-butyl2-(2-aminoethoxy)ethylcarbamate as a colorless liquid that was usedwithout further purification.

[0223] Part E

[0224] A stirred solution of 4-chloro-3-nitroquinoline (31.4 g, 0.151mol) in 500 mL of anhydrous CH₂Cl₂, under N₂, was treated withtriethylamine (43 mL, 0.308 mol) and tert-butyl2-(2-aminoethoxy)ethylcarbamate (0.151 mol). After stirring overnight,the reaction mixture was washed with H₂O (2×300 mL) and brine (300 mL).The organic portion was dried over Na₂SO₄ and concentrated to give abright yellow solid. Recrystallization from ethyl acetate/hexanes gave43.6 g of tert-butyl2-{2-[(3-nitroquinolin-4-yl)amino]ethoxy}ethylcarbamate as bright yellowcrystals.

[0225] Part F

[0226] A solution of tert-butyl2-{2-[(3-nitroquinolin-4-yl)amino]ethoxy}ethylcarbamate (7.52 g, 20.0mmol) in toluene was treated with 1.5 g of 5% Pt on carbon and shakenunder H₂ (3 Kg/cm²) for 24 h. The solution was then filtered through aCelite pad and concentrated to give 6.92 g of crude tert-butyl2-{2-[(3-aminoquinolin-4-yl)amino]ethoxy}ethylcarbamate as a yellowsyrup.

[0227] Part G

[0228] A solution of tert-butyl2-{2-[(3-aminoquinolin-4-yl)amino]ethoxy}ethylcarbamate (10.2 g, 29.5mmol) in 250 mL of anhydrous CH₂Cl₂ was cooled to 0° C. and treated withtriethylamine (4.18 mL, 30.0 mmol). Methoxypropionyl chloride (3.30 mL,30.3 mmol) was then added dropwise over 5 min. The reaction was thenwarmed to room temperature and stirring was continued for 1 h. Thereaction mixture was then concentrated under reduced pressure to give anorange solid. This was dissolved in 250 mL of EtOH and 12.5 mL oftriethylamine was added. The mixture was heated to reflux and stirredunder N₂ overnight. The reaction was then concentrated to dryness underreduced pressure and treated with 300 mL of Et₂O. The mixture was thenfiltered and the filtrate was concentrated under reduced pressure togive a brown solid. The solid was dissolved in 200 mL of hot MeOH andtreated with activated charcoal. The hot solution was filtered andconcentrated to give 11.1 g of tert-butyl2-{2-[2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethylcarbamateas a yellow syrup.

[0229] Part H

[0230] A solution of tert-butyl2-{2-[2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethylcarbamate(10.22 g, 24.7 mmol) in 250 mL of CHCl₃ was treated with3-chloroperoxybenzoic acid (MCPBA, 77%, 9.12 g, 40.8 mmol). Afterstirring 30 min, the reaction mixture was washed with 1% Na₂CO₃ solution(2×75 mL) and brine. The organic layer was then dried over Na₂SO₄ andconcentrated to give 10.6 g of tert-butyl2-{2-[2-(2-methoxyethyl)-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethylcarbamateas an orange foam that was used without further purification.

[0231] Part I

[0232] A solution of tert-butyl2-{2-[2-(2-methoxyethyl)-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethylcarbamate(10.6 g, 24.6 mmol) in 100 mL of 1,2-dichloroethane was heated to 60° C.and treated with 10 mL of concentrated NH₄OH solution. To the rapidlystirred solution was added solid p-toluenesulfonyl chloride (7.05 g,37.0 mmol) over a 10 min period. The reaction mixture was treated withan additional 1 mL concentrated NH₄OH solution and then sealed in apressure vessel and heating was continued for 2 h. The reaction mixturewas then cooled and treated with 100 mL of CHCl₃. The reaction mixturewas then washed with H₂O, 1% Na₂CO₃ solution (2×) and brine. The organicportion was dried over Na₂SO₄ and concentrated to give 10.6 g oftert-butyl2-{2-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethylcarbamateas a brown foam.

[0233] Part J

[0234] Tert-butyl2-{2-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethylcarbamate(10.6 g, 24.6 mmol) was treated with 75 mL of 2M HCl in EtOH and themixture was heated to reflux with stirring. After 1.5 h, the reactionmixture was cooled and filtered to give a gummy solid. The solid waswashed EtOH and Et₂O and dried under vacuum to give the hydrochloridesalt as a light brown solid. The free base was made by dissolving thehydrochloride salt in 50 mL of H20 and treating with 10% NaOH solution.The aqueous suspension was then concentrated to dryness and the residuewas treated with CHCl₃. The resulting salts were removed by filtrationand the filtrate was concentrated to give 3.82 g of1-[2-(2-aminoethoxy)ethyl]-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amineas a tan powder.

[0235] MS 330 (M+H)⁺;

[0236]¹H NMR (300 MHz, DMSO-d₆) δ 8.10 (d, J=8.1 Hz, 1H); 7.66 (d, J=8.2Hz, 1H); 7.40 (m, 1H); 7.25 (m, 1H); 6.88 (br s, 2H); 4.78 (t, J=5.4 Hz,2H); 3.89 (t, J=4.8 Hz, 2H); 3.84 (t, J=6.9 Hz, 2H); 3.54 (t, J=5.4 Hz,2H); 3.31 (s, 3H); 3.23 (t, J=6.6 Hz, 2H); 2.88 (t, J=5.3 Hz, 2H).

[0237] Part K

[0238]1-[2-(2-Aminoethoxy)ethyl]-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine(750 mg, 2.28 mmol) was dissolved in 30 mL of anhydrous CH₂Cl₂ andcooled to 0° C. under N₂. To the stirred solution were added Et₃N (0.64mL, 4.56 mmol) and methanesulfonyl chloride (176 μL, 2.28 mmol) and thereaction was allowed to warm to room temperature over 2 h. The reactionmixture was then quenched by addition of saturated NaHCO₃ solution (30mL). The organic layer was separated and washed with H₂O (3×25 mL) andbrine, dried over Na₂SO₄ and concentrated under reduced pressure to givea tan foam. The foam was dissolved in a minimum amount of MeOH and Et₂Owas added and a solid percipitated from the solution. The off-whitesolid was isolated by filtration and dried to yield 385 mg ofN-(2-{2-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl)methanesulfonamide.m.p. 114.0-117.0° C.;

[0239] MS 408 (M+H)⁺;

[0240]¹H NMR (300 MHz, DMSO-d₆) δ 8.05 (d, J=7.6 Hz, 1H); 7.61 (d, J=8.5Hz, 1H); 7.42 (t, J=8.5 Hz, 1H); 7.24 (t, J=7.0 Hz, 1H); 6.99 (t, J=4.4Hz, 1H); 6.51 (s, 2H); 4.76 (t, J=5.0 Hz, 2H); 3.88-3.81 (m, 4H); 3.41(t, J=5.4 Hz, 2H); 3.31 (s, 3H); 3.23 (t, J=6.9 Hz, 2H); 3.04-2.99 (m,2H); 2,81 (s, 3H);

[0241]¹³C (75 MHz, DMSO-d₆) 151.9, 145.0, 132.7, 126.7, 126.6, 121.5,120.5, 115.1, 70.5, 70.2, 69.3, 58.5, 45.4, 42.4, 27.6.

[0242] Anal. Calcd for C₁₈H₂₅N₅O₄S0.23 H₂O: %C, 52.52; %H, 6.23; %N,17.01. Found: %C, 52.55; %H, 6.17; %N, 16.66.

EXAMPLE 2N-(2-{2-[4-amino-2-(2-methoxyethyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl)methanesulfonamide

[0243]

[0244] Part A

[0245]1-[2-(2-Aminoethoxy)ethyl]-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine(10.0 g, 27.3 mmol) was dissolved in 50 mL of trifluoroacetic acid andtreated with PtO₂ (1.0 g). The reaction mixture was shaken under H₂ (3Kg/cm²). After 4 d, an additional 0.5 g of PtO₂ was added andhydrogenation was continued for an additional 3 d. The reaction was thenfiltered through Celite and concentrated under reduced pressure to givea brown oil. The oil was dissolved in 200 mL of H₂O then made basic (pH˜11) by addition of 10% NaOH solution. This was then extracted withCHCl₃ (5×75 mL) and the combined organic layers were dried over Na₂SO₄and concentrated to give 5.17 g of1-[2-(2-aminoethoxy)ethyl]-2-(2-methoxyethyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amineas a tan solid.

[0246] MS 334 (M+H)⁺;

[0247]¹H NMR (300 MHz, CDCl₃) δ 5.19 (s, 2H); 4.49 (t, J=5.4 Hz, 2H);3.84 (t, J=6.6 Hz, 2H); 3.71 (t,J=5.4 Hz, 2H), 3.36 (t, J=5.2 Hz, 2H);3.28 (s, 3H); 3.15 (t,J=6.6 Hz, 2H); 2.95 (m, 2H); 2.82 (m, 2H); 2.76(t,J=5.1 Hz, 2H); 1.84 (m, 4H), 1.47 (br s, 2H).

[0248] Part B

[0249]1-[2-(2-Aminoethoxy)ethyl]-2-(2-methoxyethyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amine(1.00 g, 3.00 mmol) was dissolved in 30 mL of anhydrous CH₂Cl₂ andcooled to 0° C. under N₂. To the stirred solution were added Et₃N (0.84mL, 6.00 mmol) and methanesulfonyl chloride (232 μL, 3.00 mmol) and thereaction was allowed to warm to room temperature overnight. The reactionmixture was then quenched by addition of saturated NaHCO₃ solution (30mL). The organic layer was separated and washed with H₂O and brine,dried over Na₂SO₄ and concentrated under reduced pressure to give ayellow solid. The solid was triturated with Et₂O and a few drops ofMeOH. The resulting white powder was isolated by filtration and furtherpurified by column chromatography (SiO₂, 3% MeOH/CHCl₃ saturated withaqueous NH₄OH) to give 389 mg ofN-(2-{2-[4-amino-2-(2-methoxyethyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl)methanesulfonamideas a white powder. m.p. 151.0-153.0° C.;

[0250] MS 412 (M+H)⁺;

[0251]¹H NMR (300 MHz, DMSO-d₆) δ 7.00 (t, J=5.4 Hz, 1H); 5.68 (s, 2H);4.44 (t, J=5.1 Hz, 2H); 3.77 (t, J=6.8 Hz, 2H); 3.68 (t, J=5.0 Hz, 2H);3.39 (t, J=5.8 Hz, 2H); 3.28 (s, 3H); 3.11-2.99 (m, 4H); 2.92 (m, 2H),2.82 (s, 3H); 2.65 (m, 2H); 1.75 (m, 4H);

[0252]¹³C (75 MHz, DMSO-d₆) 151.3, 149.3, 146.3, 138.4, 124.9, 105.6,70.6, 70.5, 70.1, 44.5, 42.4, 32.7, 27.6, 23.8, 23.1, 23.0.

[0253] Anal. Calcd for C₁₈H₂₉N₅O₄S: %C, 52.54; %H, 7.10; %N, 17.02.Found: %C, 52.47; %H, 7.22; %N, 16.83.

EXAMPLE 3N-(2-{2-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl)-N-methylmethanesulfonamide

[0254]

[0255] Part A

[0256] Sodium hydride (60% oil dispersion, 9.1 g, 228 mmol) was placedin a round bottom flask and washed with hexanes (3×) under N₂. The driedsodium hydride was treated with 800 mL of anhydrous THF. A solution oftert-butyl 2-(2-azidoethoxy)ethylcarbamate (41.9 g, 182 mmol) in 200 mLof THF was then added to the stirred sodium hydride solution over 40min. After addition was complete, the reaction was stirred an additional20 min followed by addition of methyl iodide (13.6 mL, 218 mmol). Afterstirring overnight, the reaction was quenched with 300 mL of saturatedNaHCO₃ solution. The reaction mixture was then treated with 200 mL ofH₂O and 1 L of Et₂O. The organic phase was separated and washed with H₂Oand brine. The organic portion was then dried over MgSO₄ andconcentrated under reduced pressure to give 41.9 g of tert-butyl2-(2-azidoethoxy)ethyl(methyl)carbamate as a yellow liquid.

[0257] Part B

[0258] A solution of tert-butyl 2-(2-azidoethoxy)ethyl(methyl)carbamate(41.9 g, 170 mmol) in 600 mL of MeOH was treated with 2.5 g of 10% Pd oncarbon and shaken under H₂ (3 Kg/cm²) for 24 h. The solution was thenfiltered through a Celite pad and concentrated to give 37.2 g of crudetert-butyl 2-(2-aminoethoxy)ethyl(methyl)carbamate as a light yellowliquid.

[0259] Part C

[0260] A stirred solution of 4-chloro-3-nitroquinoline (32.3 g, 155mmol) in 400 mL of anhydrous CH₂Cl₂, under N₂, was treated withtriethylamine (43.1 mL, 310 mmol) and tert-butyl2-(2-aminoethoxy)ethyl(methyl)carbamate (37.2 g, 171 mmol). Afterstirring overnight, the reaction mixture was washed with H₂O (2×300 mL)and brine (300 mL). The organic portion was dried over Na₂SO₄ andconcentrated to give a brown oil. Column chromatography (SiO₂, 33% ethylacetate/hexanes-67% ethyl acetate/hexanes) gave 46.7 g of tert-butylmethyl(2-{2-[(3-nitroquinolin-4-yl)amino]ethoxy}ethyl)carbamate as ayellow solid.

[0261] Part D

[0262] A solution of tert-butylmethyl(2-{2-[(3-nitroquinolin-4-yl)amino]ethoxy}ethyl)carbamate (6.56 g,16.8 mmol) in 75 mL of toluene was treated with 0.5 g of 5% Pt on carbonand shaken under H₂ (3 Kg/cm²) for 24 h. The solution was then filteredthrough a Celite pad and concentrated to give 6.8 g of crude tert-butyl2-{2-[(3-aminoquinolin-4-yl)amino]ethoxy}ethyl(methyl)carbamate as anorange syrup which was carried on without further purification.

[0263] Part E

[0264] A solution of tert-butyl2-{2-[(3-aminoquinolin-4-yl)amino]ethoxy}ethyl(methyl)carbamate (6.05 g,16.8 mmol) in 200 mL of anhydrous CH₂Cl₂ was cooled to 0° C. and treatedwith triethylamine (2.40 mL, 17.2 mmol). Methoxypropionyl chloride (1.72mL, 17.2 mmol) was then added dropwise over 5 min. The reaction was thenwarmed to room temperature and stirring was continued for 3 h. Thereaction mixture was then concentrated under reduced pressure to give anorange solid. This was dissolved in 200 mL of EtOH and 7.2 mL oftriethylamine was added. The mixture was heated to reflux and stirredunder N₂ overnight. The reaction was then concentrated to dryness underreduced pressure and treated with 300 mL of Et₂O. The mixture was thenfiltered and the filtrate was concentrated under reduced pressure togive a brown solid. This was dissolved in 300 mL of CH₂Cl₂ and washedwith H₂O and brine. The organic portion was dried over Na₂SO₄ andconcentrated under reduced pressure to give a brown oil. The oil wasdissolved in 100 mL of hot MeOH and treated with activated charcoal. Thehot solution was filtered and concentrated to give 7.20 g of tert-butyl2-{2-[2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl(methyl)carbamateas a yellow syrup.

[0265] Part F

[0266] A solution of tert-butyl2-{2-[2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl(methyl)carbamate(7.20 g, 16.8 mmol) in 200 mL of CH₂Cl₂ was treated with MCPBA (77%,4.32 g, 19.3 mmol). After stirring 6 h, the reaction mixture was treatedwith saturated NaHCO₃ solution and the layers were separated. Theorganic portion was washed with H₂O and brine then dried over Na₂SO₄ andconcentrated to give 7.05 g of tert-butyl2-{2-[2-(2-methoxyethyl)-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl(methyl)carbamateas a light brown solid.

[0267] Part G

[0268] A solution of tert-butyl2-{2-[2-(2-methoxyethyl)-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl(methyl)carbamate(7.05 g, 15.9 mmol) in 100 mL of 1,2-dichloroethane was heated to 80° C.and treated with 5 mL of concentrated NH₄OH solution. To the rapidlystirred solution was added solid p-toluenesulfonyl chloride (3.33 g,17.5 mmol) over a 10 min period. The reaction mixture was treated withan additional 5 mL concentrated NH₄OH solution and then sealed in apressure vessel and heating was continued for 4 h. The reaction mixturewas then cooled and treated with 100 mL of CH₂Cl₂. The reaction mixturewas then washed with H₂O, 1% Na₂CO₃ solution (3×) and brine. The organicportion was dried over Na₂SO₄ and concentrated to give 6.50 g oftert-butyl2-{2-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl(methyl)carbamateas a brown oil

[0269] Part H

[0270] Tert-butyl2-{2-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl(methyl)carbamate(6.50 g, 14.7 mmol) was dissolved in 100 mL of EtOH and treated with 20mL of 2M HCl in EtOH and the mixture was heated to reflux with stirring.After 6 h, the reaction mixture was cooled and filtered to give a gummysolid. The solid was washed with EtOH and Et₂O and dried under vacuum togive the hydrochloride salt as a light brown powder. The free base wasmade by dissolving the hydrochloride salt in 50 mL of H₂O and treatingwith 5 mL of concentrated NH₄OH. The aqueous suspension was extractedwith CHCl₃ (5×50 mL). The combined organic layers were dried over Na₂SO₄and concentrated to give 3.93 g of2-(2-methoxyethyl)-1-{2-[2-(methylamino)ethoxy]ethyl}-1H-imidazo[4,5-c]quinolin-4-amineas a tan powder.

[0271] MS 344 (M+H)⁺;

[0272]¹H NMR (300 MHz, DMSO-d₆) δ 8.07 (d, J=7.7 Hz, 1H); 7.62 (dd,J=1.0, 8.3 Hz, 1H); 7.42 (ddd, J=1.0, 7.1, 8.2 Hz, 1H); 7.22 (ddd,J=1.1, 7.1, 8.2 Hz, 1H); 6.49 (s, 2H); 4.75 (t, J=5.1 Hz, 2H); 3.83 (t,J=6.8 Hz, 4H); 3.35 (t, J=5.6 Hz, 2H); 3.30 (s, 3H); 3.21 (t, J=6.9 Hz,2H); 2.45 (t, J=5.6 Hz, 2H); 2.12 (s, 3H).

[0273] Part I

[0274]2-(2-Methoxyethyl)-1-{2-[2-(methylamino)ethoxy]ethyl}-1H-imidazo[4,5-c]quinolin-4-amine(1.00 g, 2.92 mmol) was dissolved in 30 mL of anhydrous CH₂Cl₂ andcooled to 0° C. under N₂. To the stirred solution were added Et₃N (0.81mL, 5.81 mmol) and methanesulfonyl chloride (226 μL, 2.92 mmol) and thereaction was allowed to warm to room temperature overnight. The reactionmixture was then quenched by addition of saturated NaHCO₃ solution (30mL) and CH₂Cl₂ (30 mL). The organic layer was separated and washed withH₂O and brine, dried over Na₂SO₄ and concentrated under reducedpressure. Crystallization of the residue from EtOAc and CH₂Cl₂ gave 756mg ofN-(2-{2-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl)-N-methylmethanesulfonamideas tan crystals. m.p. 145.0-146.5° C.;

[0275] MS 422 (M+H)⁺;

[0276]¹H NMR (300 MHz, DMSO-d₆) δ 8.06 (d, J=7.8 Hz, 1H); 7.61 (dd,J=0.9, 8.3 Hz, 1H); 7.42 (t, J=7.2 Hz, 1H); 7.23 (ddd, J=1.0, 7.0, 8.0Hz, 1H); 6.50 (s, 2H); 4.77 (t, J=5.0 Hz, 2H); 3.87 (t, J=5.0 Hz, 2H),3.83 (t, J=6.8 Hz, 2H); 3.48 (t, J=5.5 Hz, 2H); 3.30 (s, 3H); 3.22 (t,J=6.8 Hz, 2H); 3.13 (t, J=5.5 Hz, 2H); 2.77 (s, 3H); 2.63 (s, 3H);

[0277]¹³C NMR (75 MHz, DMSO-d₆) δ 153.9, 153.8, 147.0, 134.6, 128.6,128.5, 123.4, 122.5, 117.0, 72.4, 71.2, 60.4, 51.1, 47.3, 37.3, 37.2,29.6.

[0278] Anal. Calcd for C₁₉H₂₇N₅O₄S: %C, 54.14; %H, 6.46; %N, 16.61.Found: %C, 53.92; %H, 6.32; %N, 16.47.

EXAMPLE 4N-(2-{2-[4-amino-2-(2-methoxyethyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl)-N-methylmethanesulfonamide

[0279]

[0280] Part A

[0281]2-(2-Methoxyethyl)-1-{2-[2-(methylamino)ethoxy]ethyl}-1H-imidazo[4,5-c]quinolin-4-amine(4.22 g, 12.3 mmol) was dissolved in 25 mL of trifluoroacetic acid andtreated with PtO₂ (0.5 g). The reaction mixture was shaken under H₂ (3Kg/cm²). After 4 d, an additional 0.5 g of PtO₂ was added andhydrogenation was continued for an additional 3 d. The reaction mixturewas then filtered through Celite and concentrated under reduced pressureto give a yellow oil. The yellow oil was dissolved in 50 mL of H₂O andextracted with 50 mL of CHCl₃. The organic portion was removed anddiscarded. The aqueous portion was then made basic (pH 12) by additionof 10% NaOH solution. This was then extracted with CHCl₃ (6×50 mL) andthe combined organic layers were dried over Na₂SO₄ and concentrated to abrown oil. The brown oil was dissolved in 100 mL of hot MeOH and treatedwith 1 g of activated charcoal. The hot solution was filtered throughCelite and concentrated to dryness. The resulting gummy solid wasconcentrated several times with Et₂O to give 3.19 g of2-(2-methoxyethyl)-1-{2-[2-(methylamino)ethoxy]ethyl}-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amineas an off-white powder.

[0282] MS 348 (M+H)⁺;

[0283]¹H NMR (300 MHz, CDCl₃) δ 4.84 (s, 2H); 4.48 (t, J=5.7 Hz, 2H);3.84 (t, J=6.7 Hz, 2H); 3.70 (t,J=5.7 Hz, 2H); 3.46 (t,J=5.1 Hz, 2H);3.36 (s, 3H); 3.14 (t,J=6.7 Hz, 2H); 2.96 (m, 2H); 2.83 (m, 2H); 2.65(t, J=5.1 Hz, 2H); 2.36 (s, 3H); 1.85 (m, 4H).

[0284] Part B

[0285](2-(2-Methoxyethyl)-1-{2-[2-(methylamino)ethoxy]ethyl}-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amine(750 mg, 2.16 mmol) was dissolved in 30 mL of anhydrous CH₂Cl₂ andcooled to 0° C. under N₂. To the stirred solution were added Et₃N (0.60mL, 4.32 mmol) and methanesulfonyl chloride (167 μL, 2.16 mmol) and thereaction was allowed to warm to room temperature over 3 h. The reactionmixture was then quenched by addition of saturated NaHCO₃ solution (30mL) and CH₂Cl₂ (30 mL). The organic layer was separated and washed withH₂O and brine, dried over Na₂SO₄ and concentrated under reducedpressure. Purification by column chromatography (SiO₂, 3-5% MeOH/CHCl₃saturated with aqueous NH₄OH) gave the product as a colorless glass. Thematerial was then concentrated with iso-propyl alcohol to give a syrupwhich solidified upon standing in the freezer. The solid was dried undervacuum to give 437 mg ofN-(2-{2-[4-amino-2-(2-methoxyethyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl)-N-methylmethanesulfonamideas off-white crystals.

[0286] m.p. 115.3-117.8° C.;

[0287] MS 426 (M+H)⁺;

[0288]¹H NMR (300 MHz, DMSO-d₆) δ 5.65 (s, 2H); 4.44 (t, J=5.2 Hz, 2H);3.76 (t, J=6.9 Hz, 2H), 3.70 (t,J=5.3 Hz, 2H); 3.47 (t,J=5.5 Hz, 2H);3.27 (s, 3H); 3.15 (t,J=5.5 Hz, 2H); 3.08 (t, J=6.9 Hz, 2H); 2.93 (m,2H); 2.78 (s, 3H); 2.65 (s, 3H); 2.64 (m, 2H); 1.74 (m, 4H);

[0289]¹³C NMR (75 MHz, DMSO-d₆) δ 151.2, 149.3, 146.3, 138.5, 124.9,105.6, 70.6, 70.5, 69.2, 58.4, 49.2, 44.5, 35.4, 35.2, 32.7, 27.6, 23.8,23.1, 23.0.

[0290] Anal. Calcd for C₁₉H₂₇N₅O₄S.0.40 C₃H₈O: %C, 53.97; %H, 7.67; %N,15.58. Found: %C, 53.71; %H, 7.48; %N, 15.77.

EXAMPLE 52-Butyl-1-{2-[2-(1,1-dioxidoisothiazolidin-2-yl)ethoxy]ethyl}-1H-imidazo[4,5-c]quinolin-4-amine.

[0291]

[0292] Under a nitrogen atmosphere, chloropropylsulfonyl chloride (0.05ml, 0.46 mmol) was added dropwise to a solution of1-[2-(2-aminoethoxy)ethyl]-2-butyl-1H-imidazo[4,5-c]quinolin-4-amine(0.12 g, 0.37 mmol) and triethylamine (0.065 ml, 0.46 mmol) indichloromethane (5 ml). The reaction was stirred for 20 hours followedby removal of the solvent in vacuo. The resulting off-white solid wasdissolved in N,N-dimethylformamide (5 mL) and1,8-diazabicyclo[5.4.0]undec-7-ene (0.087 ml, 0.58 mmol) was added. Thereaction was stirred for 18 hours under an atmosphere of nitrogen andthen quenched with water and extracted with dichloromethane (2×). Theorganic fractions were combined, washed with water followed by brine,dried (Na₂SO₄), filtered, and concentrated in vacuo to provide anoff-white solid. Recrystallization from ethyl acetate yielded 0.068 g of2-butyl-1-{2-[2-(1,1-dioxidoisothiazolidin-2-yl)ethoxy]ethyl}-1H-imidazo[4,5-c]quinolin-4-amineas off-white crystals, m.p. 152-154° C.

[0293]¹H-NMR (300 MHz, DMSO-d₆): δ 8.06 (d, J=8.1 Hz, 1H), 7.62 (d,J=7.9 Hz, 1H), 7.42 (t, J=7.6 Hz, 1H), 7.23 (t, J=7.5 Hz, 1H), 6.52 (s,2H), 4.73 (t, J=4.99 Hz, 2H), 3.86 (t, J=5.0 Hz, 2H), 3.46 (t, J=5.3 Hz,2H), 3.07 (t, J=7.66 Hz, 2H), 2.97-2.87 (m, 6H), 2.04 (quintet, J=6.8Hz, 2H), 1.81 (quintet, J=7.6 Hz, 2H), 1.46 (sextet, J=7.4 Hz, 2H), 0.96(t, J=7.3 Hz, 3H);

[0294]¹³C-NMR (75 MHz, DMSO-d₆): δ 154.6, 152.9, 145.1, 133.0, 126.8,126.6, 121.6, 120.8, 115.3, 69.2, 69.1, 47.0, 45.5, 45.0, 43.7, 29.3,26.2, 21.9, 18.1, 13.7;

[0295] Anal calcd for C₂₁H₂₉N₅O₃S*0.25H₂O: %C, 57.84; %H, 6.82; %N,16.06; %S, 7.35. Found: %C, 57.90; %H, 6.79; %N, 15.92; %S, 7.55.

EXAMPLES 6-26

[0296] Part A

[0297] A solution of tert-butyl2-{2-[(3-aminoquinolin-4-yl)amino]ethoxy}ethylcarbamate (3.46 g, 10.0mmol) in 50 mL of toluene was treated with triethylorthovalerate (2.5mL, 14.5 mmol) and the reaction mixture was heated to reflux. A 25 mgportion of pyridinium hydrochloride was then added and refluxing wascontinued for 4 h. The reaction was then concentrated to dryness underreduced pressure. The residue was dissolved in 50 mL of CH₂Cl₂ andwashed with saturated NaHCO₃, H₂O and brine. The organic portion wasdried over Na₂SO₄ and concetrated to give a green oil. The green oil wasdissolved in 50 mL of hot MeOH and treated with activated charcoal. Thehot solution was filtered and concentrated to give 4.12 g of tert-butyl2-[2-(2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamate as ayellow oil.

[0298] Part B

[0299] A solution of tert-butyl2-[2-(2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamate (4.12g, 10.0 mmol) in 50 mL of CH₂Cl₂ was treated with 3-chloroperoxybenzoicacid (MCPBA, 77%, 2.5 g, 11.2 mmol). After stirring for 5 h, thereaction mixture was treated with saturated NaHCO₃ solution and thelayers were separated. The organic portion was washed with H₂O and brinethen dried over Na₂SO₄ and concentrated to give 3.68 g of tert-butyl2-[2-(2-butyl-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamateas a light brown foam.

[0300] Part C

[0301] A solution of tert-butyl2-[2-(2-butyl-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamate(3.68 g, 8.60 mmol) in 100 mL of 1,2-dichloroethane was heated to 80° C.and treated with 10 mL of concentrated NH₄OH solution. To the rapidlystirred solution was added solid p-toluenesulfonyl chloride (1.87 g,9.81 mmol) over a 10 min period. The reaction mixture was then sealed ina pressure vessel and heating was continued for 2 h. The reactionmixture was then cooled and treated with 100 mL of CH₂Cl₂. The reactionmixture was then washed with H₂O, 1% Na₂CO₃ solution (3×) and brine. Theorganic portion was dried over Na₂SO₄ and concentrated to give 3.68 g oftert-butyl2-[2-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamateas a light brown foam.

[0302] Part D

[0303] Tert-butyl2-[2-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamate(3.68 g, 8.60 mmol) was suspended in 20 mL of 2M HCl in EtOH and themixture was heated to reflux with stirring. After 3 h, the reactionmixture was concentrated to give a solid. The solid was triturated withhot EtOH (50 mL) and filtered to give 2.90 g of the product as thehydrochloride salt. The free base was made by dissolving thehydrochloride salt in 50 mL of H₂O and treating with 5 mL ofconcentrated NH₄OH. The aqueous suspension was extracted with CH₂Cl₂(3×50 mL). The combined organic layers were dried over Na₂SO₄ andconcentrated to give1-[2-(2-aminoethoxy)ethyl]-2-butyl-1H-imidazo[4,5-c]quinolin-4-amine asa tan powder.

[0304] MS 328 (M+H)⁺;

[0305]¹H NMR (300 MHz, CDCl₃) δ 7.95 (d, J=8.3 Hz, 1H); 7.83 (d, J=8.4Hz, 1H); 7.50 (m, 1H); 7.30 (m, 1H); 5.41 (s, 2H); 4.69 (t, J=5.6 Hz,2H); 3.93 (t, J=5.6 Hz, 2H); 3.39 (t,J=5.1 Hz, 2H); 2.97 (t,J=7.9 Hz,2H); 2.76 (t,J=5.1 Hz, 2H); 1.89 (m, 2H); 1.52 (m, 2H); 1.26 (br s, 2H);1.01 (t, J=7.3 Hz, 3H).

[0306] Part E

[0307] The compounds in the table below were prepared according to thesynthetic method of step (7) of Reaction Scheme II above using thefollowing general method.

[0308] The sulfonyl chloride or the sulfamoyl chloride (1.1 eq.) wasadded to a test tube containing a solution of1-[2-(2-aminoethoxy)ethyl]-2-butyl-1H-imidazo[4,5-c]quinolin-4-amine (25mg) in dichloromethane (5 mL). The test tube was capped and then placedon a shaker at ambient temperature for 18-20 hr. The solvent was removedby vacuum centrifugation. The residue was purified by semi-preparativeHPLC using the method described above. The products were verified byaccurate mass and ¹H NMR. The table below shows the structure of thefree base and the observed accurate mass (M+H). Example Accurate MassNumber Structure of Free Base (obs.) 6

420.2077 7

434.2234 8

435.2196 9

448.2387 10

468.2075 11

474.1625 12

482.2214 13

486.1967 14

493.2009 15

493.2025 16

498.2195 17

504.1861 18

518.2210 19

518.2243 20

519.2158 21

536.1917 22

544.2384 23

546.1852 24

552.1874 25

615.2848 26

542.2779

EXAMPLES 27-39

[0309] Part A

[0310] Using the general method of Part A of Examples 6-26,4-piperidineethanol (10 g, 77.4 mmol) was reacted with di-tert-butyldicarbonate (17.7 g, 81.3 mmol) to provide 13.1 g of tert-butyl4-(2-hydroxyethyl)piperidine-1-carboxylate as a clear oil.

[0311] Part B

[0312] Iodine (7.97 g) was added in three portions to a solution ofimidazole (3.89 g, 57.1 mmol) and triphenylphosphine (14.98 g, 57.1mmol) in dichloromethane (350 mL). After 5 minutes a solution of thematerial from Part A in dichloromethane (70 mL) was added. The reactionmixture was stirred at ambient temperature overnight. More iodine (7.97g) was added and the reaction was stirred at ambient temperature for 1hr. The reaction mixture was washed with saturated sodium thiosulfate(2×) and brine, dried over sodium sulfate, filtered and thenconcentrated under reduced pressure to provide an oily residue. Theresidue was purified by column chromatography (silica gel eluting with20% ethyl acetate in hexanes) to provide 15.52 g of tert-butyl4-(2-iodoethyl)piperidine-1-carboxylate as a pale yellow oil.

[0313] Part C

[0314] Under a nitrogen atmosphere,2-(1H-imidazo[4,5-c]quinolin-1-yl)butan-1-ol (6.5 g, 26.9 mmol) wasadded in three portions to a suspension of sodium hydride (1.4 g of 60%,35.0 mmol) in anhydrous N,N-dimethylformamide. The reaction mixture wasallowed to stir for 45 minutes by which time gas evolution had ceased.Tert-butyl 4-(2-iodoethyl)piperidine-1-carboxylate (10.05 g, 29.6 mmol)was added dropwise over a period of 15 minutes. The reaction mixture wasallowed to stir at ambient temperature for 2.5 hrs; then it was heatedto 100° C. and stirred overnight. Analysis by HPLC showed that thereaction was about 35% complete. Saturated ammonium chloride solutionwas added, the resulting mixture was allowed to stir for 20 minutes andthen it was extracted with ethyl acetate (2×). The ethyl acetateextracts were washed with water (2×) and then with brine, combined,dried over sodium sulfate, filtered and then concentrated under reducedpressure to provide a brown oil. The oil was purified by columnchromatography (silica gel eluting sequentially with 30% ethyl acetatein hexanes, 50% ethyl acetate in hexanes, and ethyl acetate) to provide2.2 g of tert-butyl4-{2-[2-(1H-imidazo[4,5-c]quinolin-1-yl)butoxy]ethyl}piperidine-1-carboxylate.

[0315] Part D

[0316] Using the general method of Examples 6-26 Part H, the materialfrom Part C was oxidized to provide tert-butyl4-{2-[2-(5-oxido-1H-imidazo[4,5-c]quinolin-1-yl)butoxy]ethyl}piperidine-1-carboxylateas an oil.

[0317] Part E

[0318] Ammonium hydroxide solution (20 mL) was added to a solution ofthe material from Part D in dichloromethane (20 mL). A solution of tosylchloride (0.99 g, 5.2 mmol) in dichloromethane (10 mL) was added over aperiod of 5 minutes. The resulting biphasic reaction mixture was allowedto stir overnight. The reaction mixture was diluted with chloroform andsaturated sodium bicarbonate solution. The layers were separated. Theorganic layer was dried over sodium sulfate, filtered and thenconcentrated under reduced pressure to provide a brown glass. Thismaterial was purified by column chromatography (silica gel eluting firstwith 50% ethyl acetate in hexanes and then with ethyl acetate) toprovide 1.0 g of tert-butyl4-{2-[2-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butoxy]ethyl}piperidine-1-carboxylateas pale yellow glassy foam.

[0319] Part F

[0320] Under a nitrogen atmosphere, tert-butyl4-{2-[2-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butoxy]ethyl}piperidine-1-carboxylate(1.00 g, 2.1 mmol) and 2N ethanolic hydrochloric acid (10 ml, 20 mmol)were combined and the solution was stirred at ambient temperature for 14hours. The solvent was removed in vacuo and the resulting tan solid wasdissolved in water. Saturated aqueous sodium carbonate was added untilthe pH reached 10. After extraction with dichloromethane (3×), theorganic fractions were combined, washed with brine, dried (Na₂SO₄),filtered, and the majority of the solvent was removed in vacuo. Hexanewas added to form a precipitate. Vacuum filtration yielded 0.5 g of1-{1-[(2-piperidin-4-ylethoxy)methyl]propyl}-1H-imidazo[4,5-c]quinolin-4-amineas a tan powder.

[0321]¹H-NMR (300 MHz, DMSO-d₆): δ 8.34 (bs, 1H), 8.19 (d, J=8.49, 1H),7.61 (dd, J=8.31, 1.13, 1H), 7.45-7.39 (m, 1H), 7.25-7.19 (m, 1H), 6.55(s, 2H), 5.25-5.15 (m, 1H), 4.00-3.80 (m, 2H), 3.5-3.3 (m, 2H), 2.8-2.64(m, 2H), 2.22-2.11 (m, 2H), 2.09-1.99 (m, 2H), 1.8-1.63 (bs, 1H),1.37-1.0 (m, 5H), 0.95-0.7 (m, 5H);

[0322]¹³C-NMR (75 MHz, DMSO-d₆): δ 152.8, 145.8, 140.6, 133.0, 127.8,127.0, 126.9, 121.3, 121.0, 115.5, 71.8, 68.1, 58.4, 46.1, 36.3, 33.1,32.7, 24.5, 9.9; MS (CI) m/e 368.2459 (368.2450 calcd for C₂₁H₃₀N₅O).

[0323] Part G

[0324] The compounds in the table below were prepared according to thesynthetic method of step (7) of Reaction Scheme II above using thefollowing general method.

[0325] The sulfonyl chloride or the sulfamoyl chloride (1.1 eq.) wasadded to a test tube containing a solution of1-{1-[(2-piperidin-4-ylethoxy)methyl]propyl}-1H-imidazo[4,5-c]quinolin-4-amine(25 mg) in dichloromethane (5 mL). The test tube was capped and thenplaced on a shaker at ambient temperature for 20 hr. The solvent wasremoved by vacuum centrifugation. The residue was purified bysemi-preparative HPLC using the method described above. The productswere verified by accurate mass and ¹H NMR. The table below shows thestructure of the free base and the observed accurate mass (M+H). ExampleAccurate Mass Number Structure of Free Base (obs.) 27

474.2531 28

475.2483 29

488.2647 30

508.2349 31

514.1924 32

526.2241 33

533.2315 34

538.2477 35

544.2166 36

559.2493 37

586.2166 (1) 38

592.2144 39

655.3173

EXAMPLES 40-49

[0326] Part A

[0327] A solution of tert-butyl2-{2-[(3-aminoquinolin-4-yl)amino]ethoxy}ethylcarbamate (6.92 g, 20.0mmol) in 100 mL of toluene was treated with triethylorthoformate (4.65mL, 28.0 mmol) and the reaction mixture was heated to reflux. A 100 mgportion of pyridinium hydrochloride was then added and refluxing wascontinued for 2 h. The reaction was then concentrated to dryness underreduced pressure. The residue was dissolved in 200 mL of CH₂Cl₂ andwashed with saturated NaHCO₃, H₂O and brine. The organic portion wasdried over Na₂SO₄ and concentrated to give a green oil. The green oilwas dissolved in 200 mL of hot MeOH and treated with 10 g of activatedcharcoal. The hot solution was filtered and concentrated to give 5.25 gof tert-butyl 2-[2-(1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamateas a light yellow syrup.

[0328] Part B

[0329] A solution of tert-butyl2-[2-(1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamate (5.25 g, 14.7mmol) in 200 mL of CH₂Cl₂ was treated with MCPBA (77%, 3.63 g, 16.3mmol). After stirring overnight, the reaction mixture was treated withsaturated NaHCO₃ solution and the layers were separated. The organicportion was washed with H₂O and brine then dried over Na₂SO₄ andconcentrated to give 4.60 g of tert-butyl2-[2-(5-oxido-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamate as alight brown foam.

[0330] Part C

[0331] A solution of tert-butyl2-[2-(5-oxido-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamate (4.60g, 12.4 mmol) in 150 mL of 1,2-dichloroethane was heated to 80° C. andtreated with 10 mL of concentrated NH₄OH solution. To the rapidlystirred solution was added solid p-toluenesulfonyl chloride (2.71 g,14.2 mmol) over a 10 min period. The reaction mixture was treated withan additional 2 mL of concentrated NH₄OH solution and then sealed in apressure vessel and heating was continued for 3 h. The reaction mixturewas then cooled and treated with 100 mL of CH₂Cl₂. The reaction mixturewas then washed with H₂O, 1% Na₂CO₃ solution (3×) and brine. The organicportion was dried over Na₂SO₄ and concentrated to give 4.56 g oftert-butyl2-[2-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamate as alight brown foam.

[0332] Part D

[0333] Tert-butyl2-[2-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamate (4.56g, 12.3 mmol) was dissolved in 100 mL of EtOH and treated with 30 mL of2M HCl in EtOH and the mixture was heated to reflux with stirring. After3 h, the reaction mixture was concentrated to give a solid. The solidwas triturated with hot EtOH (100 mL) and filtered to give the productas the hydrochloride salt. The free base was made by dissolving thehydrochloride salt in 50 mL of H₂O and treating with 5 mL ofconcentrated NH₄OH. The aqueous suspension was extracted with CH₂Cl₂(5×50 mL). The combined organic layers were dried over Na₂SO₄ andconcentrated to give 1.35 g of1-[2-(2-aminoethoxy)ethyl]-1H-imidazo[4,5-c]quinolin-4-amine as a tanpowder.

[0334] MS 272 (M+H)⁺;

[0335]¹H NMR (300 MHz, CDCl₃) δ 7.98 (d, J=8.2 Hz, 1H); 7.88 (s, 1H);7.84 (d, J=8.4 Hz, 1H); 7.54 (m, 1H); 7.32 (m, 1H); 5.43 (s, 2H); 4.74(t, J=5.2 Hz, 2H); 3.97 (t, J=5.2 Hz, 2H); 3.42 (t, J=5.1 Hz, 2H); 2.78(t, J=5.1 Hz, 2H); 1.10 (br s, 2H).

[0336] Part E

[0337] The compounds in the table below were prepared according to thesynthetic method of step (7) of Reaction Scheme II above using thefollowing general method.

[0338] 1-[2-(2-Aminoethoxy)ethyl]-1H-imidazo[4,5-c]quinolin-4-amine (20mg) and 1-methyl-2-pyrrolidinone (5 mL) were combined in a test tube andthen heated and sonicated to provide a solution. The sulfonyl chloride(1.1 eq.) was then added to the test tube. The test tube was capped andthen placed on a shaker at ambient temperature for 20 hr. The solventwas removed by vacuum centrifugation. The residue was purified bysemi-preparative HPLC using the method described above. The productswere verified by accurate mass and ¹H NMR. The table below shows thestructure of the free base and the observed accurate mass (M+H). ExampleAccurate Mass Number Structure of Free Base (obs.) 40

392.1781 41

412.1468 42

430.1348 43

442.1572 44

448.1259 45

462.1571 46

480.1274 47

488.1722 48

490.1224 49

496.1230

EXAMPLE 50N-[10-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)-4,7-dioxadecyl]-5-dimethylaminonaphthalene-1-sulfonamide

[0339]

[0340] Part A

[0341] 4,7-Dioxadecane-1,10-diamine (32.6 g, 0.185 mole) in acetonitrile(100 mL) was chilled in an ice bath. To this was slowly added dropwisedansyl chloride (5 g, 0.0185 mole) dissolved in acetonitrile (60 mL)over a 20 min. period. Stirring in an ice bath was continued for 1.5 hr.The reaction mixture was poured into water (about 300 mL) and extractedwith dichloromethane (2×100 mL). The combined extracts were washed withwater and dried to give an oil. The oil was purified by columnchromatography (silica gel eluting with acetonitrile containingincreasing amounts of ethanol) to provide 4.6 g ofN-(10-amino-4,7-dioxadecyl)-5-dimethylaminonaphthalene-1-sulfonamide asa viscous oil.

[0342]¹H-NMR (500 MHz, CDCl₃) 1.65 (2H, quin), 1.75 (2H, quin), 2.80(2H, t, 6.59 Hz), 2.87 (6H, s), 3.03 (2H, t, 6.1 Hz), 3.43 (2H, m), 3.47(2H, m), 3.52 (2H, m), 3.59 (2H, t, 6.22 Hz), 7.18 (1H, d, J=7.08 Hz)),7.56-7.49 (overlapping multiplets, 2H), 8.24 (dd, 1H, J=1.2, 7.3 Hz),8.31 (d, 1H), 8.53 (d, 1H).

[0343] Part B

[0344] A solution of 2,4-dichloro-3-nitroquinoline (2.71 g, 0.0115 mole)in toluene (100 mL) was cooled to 0-5° C. in an ice bath. Triethylamine(1.5 g) was added in one portion. A solution ofN-(10-amino-4,7-dioxadecyl)-5-dimethylaminonaphthalene-1-sulfonamide(4.6 g, 0.01159 mole) in toluene (60 mL) was added dropwise whilemaintaining the temperature below 10° C. The reaction was stirred at2-5° C. for 4 hrs and at a room temperature of 21° C. overnight (18hours). Thin layer chromatography (dichloromethane: ethanol) showed atrace of the amine starting material, but was mostly a bright yellowspot at the solvent front assumed to be the addition product. Thetoluene was removed by rotary evaporation to provide a viscous oil. Theoil was purified by column chromatography (silica gel,dichloromethane/ethanol) to provide 2.4 g ofN-[10-(2-chloro-3-nitro-4-quinolinyl)amino-4,7-dioxadecyl]-5-dimethylaminonaphthalene-1-sulfonamide.

[0345]¹H-NMR (CDCl₃) 1.62 (2H, quin), 2.05 (2H, quin), 2.87 (6H, s),3.03 (2H, m), 3.47 (4H, m), 3.55 (2H, m), 3.65 (2H, m), 3.73 (2H, t,5.37 Hz), 5.75 (1H, t, 4.39 Hz, NH), 6.91 (1H, t, 4.76 Hz, NH), 7.15(1H, d, 7.32 Hz), 7.30 (1H, m), 7.50 (2H, overlapping t), 7.62 (1H, m),7.82 (1H, d, 7.44 Hz), 7.88 (1H, d, 8.54 Hz), 8.22 (1H, m ), 8.29 (1H,d, 8.42), 8.52 (1H, d, 8.06 Hz).

[0346] Part C

[0347] Material from Part B (2.2 g, 0.00357 mole) was dissolved inethanol (150 mL). Catalyst (about 1 g of 5% Pt/C) was added and themixture was hydrogenated using a Parr apparatus for 30 minutes. Thinlayer chromatography (ethyl acetate: hexane 1: 1) showed that thereaction was complete. The reaction mixture was filtered to remove thecatalyst and the filtrate was evaporated to provide a sticky solid whichwas shown by NMR to be crudeN-[10-(3-amino-2-chloro-4-quinolinyl)amino-4,7-dioxadecyl]-5-dimethylaminonaphthalene-1-sulfonamide.It was used without further purification.

[0348]¹H-NMR (500 MHz, CDCl₃) 1.60 (2H, quin), 1.90 (2H, quin), 2.87(6H, s, NMe₂), 3.00 (2H, br s), 3.45 (4H, m), 3.53 (2H, m), 3.62 (2H, t,5.62 Hz), 3.71 (4.30 (2H, br S, NH₂ ), 5.85 (1H, br s, NH), 7.11 (1H, d,J=7.32 Hz), 7.35 (1H, m), 7.44-7.48 (3H, m), 7.82 (1H, d), 8.18 (1H, dd,J=1.1, 7.2 Hz), 8.30 (1H, d, 8.66 Hz), 8.49 (1H, d, 8.54 Hz).

[0349]¹³C-NMR (125 MHz) 28.48 (CH₂), 30.08 (CH₂), 41.93 (CH₂), 45.27(CH₃), 45.28 (CH₂), 69.75 (CH₂), 69.83 (CH₂), 70.08 (CH₂), 70.38 (CH₂),114.99 (CH), 118.84 (CH), 120.84 (CH), 123.02 (CH), 123.50 (C), 125.67(CH), 126.22 (CH), 128.01 (CH), 128.57 (C) 128.67 (CH), 129.22 (CH),129.52 (C), 129.74 (C), 130.09 (CH), 134.72 (C), 137.17 (C), 141.82 (C),142.03 (C), 151.75 (C).

[0350] Part D

[0351] A portion (1 g, 1.708 mmol) of the material from Part C wasdissolved in tetrahydrofuran (30 mL) and then cooled in an ice-bath toabout 5° C. Freshly distilled acetyl chloride (0.13 g, 1.78 mmol) wasadded with stirring. The yellow solid which immediately precipitated wasisolated by filtration and washed with tetrahydrofuran. Standing in airgave an oily solid (possibly hygroscopic). FAB (fast atom bombardment)mass spectrum suggested that this was the desiredN-[10-(3-acetamido-2-chloro-4-quinolinyl)amino-4,7-dioxadecyl]-5-dimethylaminonaphthalene-1-sulfonamidehydrochloride together with an undetermined amount of starting material.This solid was carried on to Part E without additional purification.

[0352] Part E

[0353] The crude salt from Part D was dissolved in dry methanolcontaining 7% ammonia (20 mL). The solution was heated at 150° C. in abomb for 6½ hrs. The reaction mixture was cooled and then concentrated.The residue was combined with acetone. Undissolved material was removedby filtration. The filtrate was concentrated and the residue waspurified by column chromatography (silica gel; ethanol/dichloromethane)to provide 0.45 g of a brown oil.

[0354]¹H-NMR (400 MHz, CDCl₃) 1.53 (2H, t, 7.08 Hz), 2.05 (2H, m), 2.45(3H, s), 2.70 (6H, s), 2.90 (2H, t, 5.98 Hz), 3.30 (8H, br, m), 4.40(2H, t, 6.59 Hz), 5.75 (2H, br s NH₂), 6.65 (1H, br s NHSO₂), 7.00 (1H,d, 7.54 Hz), 7.14 (1H, t, 8.06 Hz), 7.30 (3H, m), 7.64 (1H, d, 8.30 Hz),7.88 (1H, d, 8.18 Hz), 8.06 (1H, d, 7.33 Hz), 8.24 (1H, d, 8.54 Hz),8.36 (1H, d, 8.55 Hz).

[0355] This material was then purified by high performance liquidchromatography using a Bondapak C18 12.5 nm reverse phase column(available from Waters, Milford, Mass.) eluting with a compositegradient of acetonitrile in water to provide the desired product.

Cytokine Induction in Human Cells

[0356] An in vitro human blood cell system is used to assess cytokineinduction. Activity is based on the measurement of interferon and tumornecrosis factor (α) (IFN and TNF, respectively) secreted into culturemedia as described by Testerman et. al. In “Cytokine Induction by theImmunomodulators Imiquimod and S-27609”, Journal of Leukocyte Biology,58, 365-372 (September, 1995).

[0357] Blood Cell Preparation for Culture

[0358] Whole blood from healthy human donors is collected byvenipuncture into EDTA vacutainer tubes. Peripheral blood mononuclearcells (PBMCs) are separated from whole blood by density gradientcentrifugation using Histopaque®-1077. The PBMCs are washed twice withHank's Balanced Salts Solution and then are suspended at 3-4×10⁶cells/mL in RPMI complete. The PBMC suspension is added to 48 well flatbottom sterile tissue culture plates (Costar, Cambridge, Mass. or BectonDickinson Labware, Lincoln Park, N.J.) containing an equal volume ofRPMI complete media containing test compound.

[0359] Compound Preparation

[0360] The compounds are solubilized in dimethyl sulfoxide (DMSO). TheDMSO concentration should not exceed a final concentration of 1% foraddition to the culture wells.

[0361] Incubation

[0362] The solution of test compound is added to the first wellcontaining RPMI complete and serial dilutions are made in the wells. ThePBMC suspension is then added to the wells in an equal volume, bringingthe test compound concentrations to the desired range. The finalconcentration of PBMC suspension is 1.5-2×10⁶ cells/mL. The plates arecovered with sterile plastic lids, mixed gently and then incubated for18 to 24 hours at 37° C. in a 5% carbon dioxide atmosphere.

[0363] Separation

[0364] Following incubation the plates are centrifuged for 5-10 minutesat 1000 rpm (˜200× g) at 4° C. The cell-free culture supernatant isremoved with a sterile polypropylene pipet and transferred to sterilepolypropylene tubes. Samples are maintained at -30 to -70° C. untilanalysis. The samples are analyzed for interferon-α and for tumornecrosis factor-α by ELISA.

[0365] Interferon (α) and Tumor Necrosis Factor (α) Analysis by ELISA

[0366] Interferon-α concentration is determined by ELISA using a HumanMulti-Species kit from PBL Biomedical Laboratories, New Brunswick, N.J.Results are expressed in pg/mL.

[0367] Tumor necrosis factor-α concentration is determined using ELISAkits available from Genzyme, Cambridge, Mass.; R&D Systems, Minneapolis,Minn.; or Pharmingen, San Diego, Calif. Results are expressed in pg/mL.

[0368] The table below lists the lowest concentration found to induceinterferon and the lowest concentration found to induce tumor necrosisfactor for each compound. A “*” indicates that no induction was seen atany of the tested concentrations; generally the highest concentrationtested was 10 or 30 μM. Cytokine Induction in Human Cells Example LowestEffective Concentration (μM) Number Interferon Tumor Necrosis Factor 30.01 0.12 6 0.001 1 7 0.01 1 8 0.01 1 9 0.1 1 10 1 10 11 1 10 12 0.1 1013 1 10 14 1 10 15 10 10 16 1 10 17 1 10 18 * 10 19 * 10 20 1 10 21 1010 22 0.0001 10 23 0.0001 10 24 0.0001 10 25 0.0001 * 26 0.01 10 27 0.11 28 0.1 1 29 1 10 30 1 10 31 1 10 32 1 1 33 1 1 34 1 1 35 1 1 36 1 1037 0.1 1 38 * * 39 1 * 41 10 1 42 10 1 43 10 10 44 1 10 45 * * 46 * *47 * * 48 * 10 49 * 10 50 1.11 *

What is claimed is:
 1. A compound of the formula (I):

wherein: X is —CHR₅—, —CHR₅-alkyl-, or —CHR₅-alkenyl-; R₁ is selectedfrom the group consisting of: —R₄—NR₃—SO₂—R₆-alkyl;—R₄—NR₃—SO₂—R₆-alkenyl; —R₄—NR₃—SO₂—R₆-aryl; —R₄—NR₃—SO₂-R₆-heteroaryl;—R₄—NR₃—SO₂-R₆-heterocyclyl; —R₄—NR₃—SO₂-R₇; —R₄—NR₃—SO₂—NR₅—R₆-alkyl;—R₄—NR₃—SO₂—NR₅—R₆-alkenyl; —R₄—NR₃—SO₂—NR₅—R₆-aryl;—R₄—NR₃—SO₂—NR₅—R₆-heteroaryl; —R₄—NR₃—SO₂—NRs—R₆-heterocyclyl; and—R₄—NR₃—SO₂—NH₂; R₂ is selected from the group consisting of: -hydrogen;-alkyl; -alkenyl; -aryl; -heteroaryl; -heterocyclyl; -alkyl-Y-alkyl;-alkyl-Y-alkenyl; -alkyl-Y-aryl; and -alkyl or alkenyl substituted byone or more substituents selected from the group consisting of: —OH;-halogen; —N(R₅)₂; —CO—N(R₅)₂; —CO—C₁₋₁₀ alkyl; —CO—O—C₁₋₁₀ alkyl; —N₃;-aryl; -heteroaryl; -heterocyclyl; —CO-aryl; and —CO-heteroaryl; Y is—O— or —S(O)₀₋₂—; R₃ is H, C₁₋₁₀ alkyl, or arylalkyl; each R₄ isindependently alkyl or alkenyl, which may be interrupted by one or more—O— groups; or R₃ and R₄ can join together to form a ring; each R₅ isindependently H, C₁₋₁₀ alkyl, or C₂₋₁₀ alkenyl; R₆ is a bond, alkyl, oralkenyl, which may be interrupted by one or more —O— groups; R₇ is C₁₋₁₀alkyl; or R₃ and R₇ can join together to form a ring; n is 0 to 4; andeach R present is independently selected from the group consisting ofC₁₋₁₀ alkyl, C₁₋₁₀ alkoxy, hydroxy, halogen and trifluoromethyl; or apharmaceutically acceptable salt thereof.
 2. A compound or salt of claim1 wherein X is —CH(alkyl)(alkyl)-, wherein the alkyl groups can be thesame or different.
 3. A compound or salt of claim 1 wherein X is—CH₂—CH₂—.
 4. A compound or salt of claim 1 wherein X is—CH(C₂H₅)(CH₂)—.
 5. A compound or salt of claim 1 wherein R₂ is H.
 6. Acompound or salt of claim 1 wherein R₂ is alkyl.
 7. A compound or saltof claim 1 wherein R₂ is alkyl-O-alkyl.
 8. A compound or salt of claim 1wherein R₃ and R₄ join to form a heterocyclic ring.
 9. A compound orsalt of claim 1 wherein R₁ is —R₄—NR₃—SO₂-R₆-aryl.
 10. A compoundselected from the group consisting of:N-(2-{2-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl)methanesulfonamide;N-(2-{2-[4-amino-2-(2-methoxyethyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl)methanesulfonamide;N-(2-{2-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl)-N-methylmethanesulfonamide;N-(2-{2-[4-amino-2-(2-methoxyethyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl)-N-methylmethanesulfonamide;2-butyl-1-{2-[2-(1,1-dioxidoisothiazolidin-2-yl)ethoxy]ethyl}-1H-imidazo[4,5-c]quinolin-4-amine;andN-[10-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)-4,7-dioxadecyl]-5-dimethylaminonaphthalene-1-sulfonamide;or a pharmaceutically acceptable salt thereof.
 11. A compound of theformula (II)

wherein: X is —CHR₅—, —CHR₅-alkyl-, or —CHR₅-alkenyl-; R₁ is selectedfrom the group consisting of: —R₄—NR₃—SO₂—R₆-alkyl;—R₄—NR₃—SO₂—R₆-alkenyl; —R₄—NR₃—SO₂—R₆-aryl; —R₄—NR₃—SO₂—R₆-heteroaryl;—R₄—NR₃—SO₂—R₆-heterocyclyl; —R₄—NR₃—SO₂—R₇; —R₄—NR₃—SO₂—NR₅—R₆-alkyl;—R₄—NR₃—SO₂—NR₅—R₆-alkenyl; —R₄—NR₃—SO₂—NR₅—R₆-aryl;—R₄—NR₃—SO₂—NR₅—R₆-heteroaryl; —R₄—NR₃—SO₂—NR₅—R₆-heterocyclyl; and—R₄—NR₃—SO₂—NH₂; R₂ is selected from the group consisting of: -hydrogen;-alkyl; -alkenyl; -aryl; -heteroaryl; -heterocyclyl; -alkyl-Y-alkyl;-alkyl-Y-alkenyl; -alkyl-Y-aryl; and -alkyl or alkenyl substituted byone or more substituents selected from the group consisting of: —OH;-halogen; —N(R₅)₂; —CO—N(R₅)₂; —CO—C₁₋₁₀ alkyl; —CO—O—C₁₋₁₀ alkyl; —N₃;-aryl; -heteroaryl; -heterocyclyl; —CO-aryl; and —CO-heteroaryl; Y is—O— or —S(O)₀₋₂—; R₃ is H, C₁₋₁₀ alkyl, or arylalkyl; each R₄ isindependently alkyl or alkenyl, which may be interrupted by one or more—O— groups; or R₃ and R₄ can join together to form a ring; each R₅ isindependently H, C₁₋₁₀ alkyl, or C₂₋₁₀ alkenyl; R₆ is a bond, alkyl, oralkenyl, which may be interrupted by one or more —O— groups; R₇ is C₁₋₁₀alkyl; or R₃ and R₇ can join together to form a ring; n is 0 to 4; andeach R present is independently selected from the group consisting ofC₁₋₁₀ alkyl, C₁₋₁₀ alkoxy, hydroxy, halogen, and trifluoromethyl; or apharmaceutically acceptable salt thereof.
 12. A compound or salt ofclaim 11 wherein R₂ is H or alkyl.
 13. A compound or salt of claim 11wherein R₂ is -alkyl-O-alkyl.
 14. A pharmaceutical compositioncomprising a therapeutically effective amount of a compound or salt ofclaim 1 and a pharmaceutically acceptable carrier.
 15. A method ofinducing cytokine biosynthesis in an animal comprising administering atherapeutically effective amount of a compound or salt of claim 1 to theanimal.
 16. The method of claim 15 wherein the cytokine is IFN-α.
 17. Amethod of treating a viral disease in an animal comprising administeringa therapeutically effective amount of a compound or salt of claim 1 tothe animal.
 18. A method of treating a neoplastic disease in an animalcomprising administering a therapeutically effective amount of acompound or salt of claim 1 to the animal.
 19. A compound of the formula(III):

wherein X is —CHR₅—, —CHR₅-alkyl-, or —CHR₅-alkenyl-; R₁ is selectedfrom the group consisting of: —R₄—NR₃—SO₂—R₆-alkyl;—R₄—NR₃—SO₂—R₆-alkenyl; —R₄—NR₃—SO₂—R₆-aryl; —R₄—NR₃—SO₂—R₆-heteroaryl;—R₄—NR₃—SO₂—R₆-heterocyclyl; —R₄—NR₃—SO₂—R₇; —R₄—NR₃—SO₂—NR₅—R₆-alkyl;—R₄—NR₃—SO₂—NR₅—R₆-alkenyl; —R₄—NR₃—SO₂—NR₅—R₆-aryl;—R₄—NR₃—SO₂—NR₅—R₆-heteroaryl; —R₄—NR₃—SO₂—NR₅—R₆-heterocyclyl; and—R₄—NR₃—SO₂—NH₂; R₂ is selected from the group consisting of: -hydrogen;-alkyl; -alkenyl; -aryl; -heteroaryl; -heterocyclyl; -alkyl-Y-alkyl;-alkyl-Y-alkenyl; -alkyl-Y-aryl; and -alkyl or alkenyl substituted byone or more substituents selected from the group consisting of: —OH;-halogen; —N(R₅)₂; —CO—N(R₅)₂; —CO—C₁₋₁₀ alkyl; —CO—O—C₁₋₁₀ alkyl; —N₃;-aryl; -heteroaryl; -heterocyclyl; —CO-aryl; and —CO-heteroaryl; Y is—O— or —S(O)₀₋₂—; R₃ is H, C₁₋₁₀ alkyl, or arylalkyl; each R₄ isindependently alkyl or alkenyl, which may be interrupted by one or more—O— groups; or R₄ and R₃ can join to form a ring; each R₅ isindependently H, C₁₋₁₀ alkyl, or C₂₋₁₀ alkenyl; R₆ is a bond, or isalkyl or alkenyl, which may be interrupted by one or more —O— groups; R₇is C₁₋₁₀ alkyl; or R₃ and R₇ can join together to form a ring; n is 0 to4; and each R present is independently selected from the groupconsisting of C₁₋₁₀ alkyl, C₁₋₁₀ alkoxy, hydroxy, halogen andtrifluoromethyl; or a pharmaceutically acceptable salt thereof.
 20. Apharmaceutical composition comprising a therapeutically effective amountof a compound or salt of claim 11 and a pharmaceutically acceptablecarrier.
 21. A method of inducing cytokine biosynthesis in an animalcomprising administering a therapeutically effective amount of acompound or salt of claim 11 to the animal.
 22. The method of claim 21wherein the cytokine is IFN-α.
 23. A method of treating a viral diseasein an animal comprising administering a therapeutically effective amountof a compound or salt of claim 11 to the animal.
 24. A method oftreating a neoplastic disease in an animal comprising administering atherapeutically effective amount of a compound or salt of claim 11 tothe animal.